N6 heterocyclic 5&#39; modified adenosine derivatives

ABSTRACT

N 6  heterocyclic 5′ modified adenosine derivatives that are adenosine A 1  receptor partial or full agonists, and as such, are useful for modifying cardiac activity, modifying adipocyte function, treating central nervous system disorders, and treating diabetic disorders and obesity in mammals, and especially in humans.

BACKGROUND OF THE INVENTION

[0001] (1) Field of the Invention

[0002] There is provided useful drugs and pro-drugs that are N⁶heterocyclic 5′ modified adenosine derivatives. The compositions of thisinvention are selective, partial or full adenosine A₁ receptor agonists,and as such, are useful for modifying cardiac activity, modifyingadipocyte function, treating central nervous system disorders, andtreating diabetic disorders and obesity in mammals, and especially inhumans.

[0003] (2) Description of the Art

[0004] There are at least two subtypes of adenosine receptors in theheart: A₁ and A_(2A). Each subtype affects different physiologicalfunctions. The A₁ adenosine receptor mediates two distinct physiologicalresponses. Inhibition of the cardiostimulatory effects of catecholamineare mediated via the inhibition of adenylate cyclase, whereas the directeffects to slow the heart rate (HR) and to prolong impulse propagationthrough the AV node are due in great part to activation of I_(KAdo). (B.Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 andJ. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997)P 2-10). Both, the anti-β-adrenergic action and direct depressanteffects on SA and AV nodal function are mediated by the A₁ receptor;there is no role for the A_(2A) receptor in this response to adenosine.A_(2A) receptors mediate the coronary vasodilatation caused byadenosine. Stimulation of the A₁ adenosine receptor accordingly shortensthe duration and decreases the amplitude of the action potential of AVnodal cells, and hence prolongs the refractory period of the AV nodalcell. The consequence of these effects is to limit the number ofimpulses conducted from the atria to the ventricles. This forms thebasis of the clinical utility of A₁ receptor agonists for the treatmentof supraventricular tachycardias, including termination of nodalre-entrant tachycardias, and control of ventricular rate during atrialfibrillation and flutter.

[0005] A clinical utility of A₁ agonists therefore is in the treatmentof acute and chronic disorders of heart rhythm, especially thosediseases characterized by rapid heart rate where the rate is driven byabnormalities in the sinoatrial, atria, and AV nodal tissues. Suchdisorders include but are not limited to atrial fibrillation,supraventricular tachycardia and atrial flutter. Exposure to A₁ agonistscauses a reduction in the heart rate and a regularization of theabnormal rhythm thereby improving cardiovascular function.

[0006] A₁ agonists, through their ability to inhibit the effects ofcatecholamines, decrease cellular cAMP, and thus, should have beneficialeffects in the failing heart where increased sympathetic tone increasescellular cAMP levels. The latter has been shown to be associated withincreased likelihood of ventricular arrhythmias and sudden death. All ofthe above concepts are discussed in reviews regarding the effects ofadenosine on cardiac electrophysiology (see B. Lerman and L.Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 and J. C. Shryockand L. Belardinelli, Am. J. Cardiology, Vol. 79 (1997) P 2-10).

[0007] A controversial area in the field of A₁ adenosine agonism is thatthe benefit of preconditioning of the heart prior to ischeria may be dueto binding of adenosine to the A₁ receptor. Evidence for this hypothesiscomes from a rabbit ischemia model wherein2-chloro-N6-cyclopentyladenosine (CCPA) and R-PIA were administeredprior to ischemia providing protection with respect to infarct size (J.D. Thornton et al. Circulation Vol. 85 (1992) 659-665).

[0008] A₁ agonists, as a result of their inhibitory action on cyclic AMPgeneration, have antilipolytic effects in adipocytes that leads to adecreased release of nonesterified fatty acids (NEFA) (E. A. van Schaicket al J. Pharmacokinetics and Biopharmaceutics, Vol. 25 (1997) p 673-694and P. Strong Clinical Science Vol. 84 (1993) p. 663-669).Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by aninsulin resistance that results in hyperglycemia. Factors contributingto the observed hyperglycemia are a lack of normal glucose uptake andactivation of skeletal muscle glycogen synthase (GS). Elevated levels ofNEFA have been shown to inhibit insulin-stimulated glucose uptake andglycogen synthesis ( D. Thiebaud et al Metab. Clin. Exp. Vol. 31 (1982)p 1128-1136 and G. Boden et al J. Clin. Invest. Vol. 93 (1994) p2438-2446). The hypothesis of a glucose fatty acid cycle was proposed byP. J. Randle as early as 1963 (P. J. Randle et al Lancet (1963) p.785-789). A tenet of this hypothesis would be that limiting the supplyof fatty acids to the peripheral tissues should promote carbohydrateutilization (P. Strong et al Clinical Science Vol. 84 (1993) p.663-669).

[0009] The benefit of an A₁ agonist in central nervous disorders hasbeen reviewed and the content are included herein by reference (L. J. S.Knutsen and T. F. Murray In Purinergic Approaches in ExperimentalTherapeutics, Eds. K. A. Jacobson and M. F. Jarvis (1997) Wiley-Liss,N.Y., P 423-470). Briefly, based on experimental models of epilepsy, amixed A₂A: A₁ agonist, metrifudil, has been shown to be a potentanticonvulsant against seizures induced by the inverse benzodiazepineagonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM,H. Klitgaard Eur. J. Pharmacol. (1993) Vol. 224 p. 221-228). In otherstudies using CGS 21680, an A_(2A) agonist, it was concluded that theanticonvulsant activity was attributed to activation of the A₁ receptor(G. Zhang et al. Eur. J. Pharmacol. Vol. 255 (1994) p. 239-243).Furthermore, A₁ adenosine selective agonists have been shown to haveanticonvulsant activity in the DMCM model (L. J. S. Knutsen In Adenosineand Adenne Nucleotides: From Molecular Biology to IntegrativePhysiology; eds. L. Belardinelli and A. Pelleg, Kluwer: Boston, 1995, pp479-487). A second area where an A₁ adenosine agonist has a benefit isin animal models of forebrain ishemia as demonstrated by Knutsen et al(J. Med. Chem. Vol. 42 (1999) p. 3463-3477). The benefit inneuroprotection is believed to be is in part due to the inhibition ofthe release of excitatory amino acids (ibid).

[0010] There are a number of full A₁ agonists disclosed in the priorart. However, the agonists disclosed are generally in the forms that arenot useful in the mammalian body. Because useful forms of A₁ agonistsmay not always be stable, soluble or they may have other properties thatmake their incorporation into therapeutic dosage forms difficult, it isoften necessary to identify compositions that are more easilyincorporated into therapeutic dosage forms in order to provide thedesired therapeutic effect. Also, these agonists fail as usefultherapeutics due to side effects caused by the non-selective stimulationof the A₁ adenosine receptor in all biologically available tissues andthe desensitization of the desired response preempting their use aschronic agents. Therefore, there remains a need for specific andselective A₁ agonists, precursors and/or pro-drugs that are converted inthe body into useful therapeutic compositions.

SUMMARY OF THE INVENTION

[0011] In one aspect, this invention includes heterocyclic 5′ modifiedadenosine derivative compositions that are useful partial or fulladenosine A₁ receptor agonists.

[0012] In another aspect, this invention includes pharmaceuticalcompositions including one or more heterocyclic 5′ modified adenosinederivative compositions that are well tolerated with few side effects.

[0013] In still another embodiment, this invention includes heterocyclic5′ modified adenosine derivatives having the formula:

[0014] In yet another embodiment, this invention includes methods foradministering compositions of this invention to mammals, and especiallyto humans, to modify cardiac activity, to modify adipocyte function, totreat central nervous system disorders, and to treat diabetic disorders.

[0015] In a further embodiment, this invention is pharmaceuticalcompositions of matter comprising at least one composition of thisinvention and one or more pharmaceutical excipients.

DESCRIPTION OF THE FIGURES

[0016]FIGS. 1A, 1B, and 1C are plots of the concentration-responserelationships for the negative chronotropic (decrease of atrial rate,panel A), shortening of atrial monophasic action potential (MAP, panelB), and negative dromotropic (increase of stimulus to His-bundleconduction time, panel C) effects of Compound 6, CPA and CCPA. Eachpoint represents the means±SEM of single determination in each of fourhearts. Second degree AV block occurred in all hearts in the presence of30 nM CPA.

[0017]FIG. 2 is chart of antagonism by CPX (50 nM), an A₁ antagonist, ofthe prolongation of the stimulus to His-bundle interval (S—H interval)caused by Compound 6 in guinea pig isolated hearts paced at actual cyclelength of 300 msec. Bars represent the means±SEM of singledeterminations from each of four hearts. The attenuation by CPX of theeffect of Compound 6 was significant (P<0.05), indicating that Compound6 acts by activating A₁ receptors in the AV node.

[0018]FIG. 3 is a chart representing antagonism by Compound 6 (2 and 10μm) of the stimulus to His-bundle interval prolongation caused by thefill agonist CPA in guinea pig isolated perfused hearts paced at anatrial cycle length of 300 msec. Bars represent the means±SEM of singledeterminations from each of four hearts.

DESCRIPTION OF THE CURRENT EMBODIMENT

[0019] This invention includes a class of heterocyclic 5′ modifiedadenosine derivatives having the formula:

[0020] wherein X¹═O, S, NR⁶; Y═O, S, N—CN, N—OR′; Z═O, S, NR⁸;

[0021] R¹ is a monocyclic or polycyclic heterocyclic group containingfrom 3 to 15 carbon atoms, wherein at least one carbon atom issubstituted with an atom or molecule selected from the group consistingof N, O, P and S—(O)₀₋₂ and wherein R¹ does not contain an epoxidegroup;

[0022] R² is selected from the group consisting of hydrogen, halo, CF₃,and cyano;

[0023] R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′, and R″ areindependently selected from the group consisting of C₁₋₁₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl,alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl are optionallysubstituted with 1 to 3 substituents independently selected from thegroup of halo, NO₂, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰,N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²²,SO₂NR²⁰CON(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CONR²⁰)₂, NR²⁰C(NR²⁰)NHR²³,COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²²,OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and eachoptional heteroaryl, aryl, and heterocyclyl substituent is furtheroptionally substituted with halo, NO₂, alkyl, CF₃, amino, mono- or di-aLkylamino, alkyl or aryl or heteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²²,COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, OR²⁰;

[0024] R⁵ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl,alkenyl, alkynyl, aryl, heterocyclyl and heteroaryl are optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of halo, alkyl, NO₂, heterocyclyl, aryl,heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,S(O)₃R²⁰, P(O)(OR²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂,NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰,CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²²,OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and each optional alkyl,heteroaryl, aryl, and heterocyclyl substituent is further optionallysubstituted with halo, NO₂, alkyl, CF₃, amino, mono- or di- alkylamino,alkyl or aryl or heteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰,CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂,SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;

[0025] R⁶ is selected from the group consisting of H, C₁, alkyl and aryloptionally substituted with halo, CN, CF₃, OR²⁰ and N(R²⁰)₂, with theproviso that when Z=NR⁸ then R⁶ and R⁸ may bond to form a 5 or 6membered saturated or unsaturated ring;

[0026] R⁷ and R⁸ are independently selected from the group consisting ofH, and C₁-C₁₅ alkyl optionally substituted with one aryl substituentthat is optionally substituted with halo or CF₃;

[0027] R²⁰ is selected from the group consisting of H, C₁₋₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, wherein thealkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituentsare optionally substituted with from 1 to 3 substituents independentlyselected from halo, alkyl, mono- or dialkylamino, aLkyl or aryl orheteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl; and

[0028] R²² is selected from the group consisting of hydrogen, C₁₋₁₅aLkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroarylsubstituents are optionally substituted with from 1 to 3 substituentsindependently selected from halo, alkyl, mono- or dialkylamino, alkyl oraryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl,wherein when Z=NR⁸ or when X¹=NR⁶ then R⁶ and R⁸ may bond to form a 4 or5 or 6 membered saturated or unsaturated ring and when X¹═NR⁶ and Y═O,then R⁵ and R⁶ may bond to form a 5 membered ring wherein R⁵ and R⁶together form C═C.

[0029] In one class of preferred compositions, X¹═O; Y═O or S; Z═NRB; R³and R⁴ are each independently selected from the group consisting ofhydrogen, —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are eachindependently selected from the group consisting of hydrogen, and C₁₋₆alkyl such as methyl, isopropyl, or cyclopentyl; R⁵ is selected from thegroup consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and aryl, which alkyl,alkenyl, and aryl, are each optionally substituted with from 1 to 2substituents independently selected from the group of halo, alkyl, aryl,heteroaryl, CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰), S(O)₃R²⁰,NR²⁰COR²², NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and each optional alkyl,and aryl substituent is optionally substituted with halo, alkyl, CF₃,CO₂R²⁰, S(O)₃R²⁰, CN, or OR²⁰; R⁸ is selected from the group consistingof H, and C₁-C₃ alkyl; and R₂₀ is a selected from the group consistingof H, Cl, alkyl such as methyl, which alkyl is optionally substitutedwith aryl wherein when Z═NR⁸ then R⁵ and R⁸ may bond to form a 4 or 5 or6 membered saturated ring. In the class of compounds above, R² is morepreferably hydrogen, Y is more preferably O or S, R⁸ is more preferablymethyl or hydrogen, R⁵ is more preferably selected from the groupconsisting of methyl, ethyl, n-propyl, n-butyl, cyclopentyl, benzyl,(4-fluorophenylmethyl), isopropyl, cyclopropyl, cyclohexyl, allyl,2-carboethoxyethyl, carbomethoxymethyl, 2-phenylcyclopropyl, cyclobutyl,2-benzyloxycyclopentyl, 2hydroxycyclopentyl, 2-carbomethoxycyclopentyl,2-(3-carboethoxy-norbom-5-enyl), 2-(3-carboxy-norbom-5-enyl),2-(3-carboethoxy-norbomyl), and 2-carboxycyclopentyl and R⁸ is morepreferably methyl or, when Z═NR⁸, then R⁵ and RI may bond -to form a 5or 6 membered saturated ring.

[0030] In another class of preferred compositions, X¹ is NR⁶; Y═O or S;Z═O; R² is H; R³ and R⁴ are independently selected from the groupconsisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′, and R″ areeach methyl; R⁵ is selected from the group consisting of C₁₋₈ alkyl, C₂,alkenyl, and aryl, which alkyl, alkenyl, and aryl, are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, NR²⁰COR²², NR²⁰CON(R²⁰)₂, CO₂R²⁰,CON(R²⁰)₂, and wherein each optional alkyl, and aryl substituent isoptionally substituted with halo, alkyl, CF₃, CO₂R²⁰, S(O)₃R²⁰, CN, orOR²⁰; R⁶ is selected from the group consisting of H, and C₁₋₃ alkylwherein when X═NR⁶ then R⁵ and R⁶ may bond to form a 4 or 5 or 6membered saturated or unsaturated ring. In the preferred class ofcompounds above, R³ and R⁴ are more preferably each hydrogen, R⁵ is a Cl₈ alkyl such as methyl or cyclopentyl, R⁶ is hydrogen, or when X¹ 50NR⁶, and Y═O, then and R⁵ and R⁶ may bond to form a 5 memberedunsaturated ring wherein R⁵ and R⁶ together form CH═CH.

[0031] In still another class of preferred compositions, X¹═S; Y═O or S;Z═NR⁸; R² is H; R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, —(CO)—R′ and —(CO)—R″, wherein R′ and R″ areeach methyl; Rl is selected from the group consisting of C₁₋₈ alkyl,C₂₋₈ alkenyl, and aryl, which alkyl, alkenyl and aryl, are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, NR²⁰COR²², NR²⁰CON(R²⁰)₂, CO₂R²⁰,CON²⁰)₂, and wherein each optional alkyl and aryl substituent is flrtheroptionally substituted with halo, alkyl, CF₃, CO₂R²⁰, S(O)₃R²⁰, CN, orOR²⁰; and R⁸ is selected from the group consisting of H, and C₁-C₃alkyl. In the class of compounds above, R³ and R⁴ are more preferablyeach hydrogen, R⁵ is preferably a C₁₋₈ alkyl such as methyl orcyclopentyl that is optionally substituted with 1 substituent selectedfrom the group consisting of aryl, OR²⁰, CO₂R²⁰, CON(R²⁰)₂, and whereineach optional aryl substituent is optionally substituted with halo,alkyl, CF₃, CO₂R²⁰, and R⁸ is preferably hydrogen.

[0032] In yet another class of preferred compositions, X¹═NR⁶; Y═O or S;Z═NR⁸; R² is H; R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein R′, and R″ areeach methyl; R⁵ is selected from the group consisting of C₁₋₈ alkyl,C₂₋₈, alkenyl, and aryl, which alkyl, alkenyl, and aryl, are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, NR²⁰COR²², NR²⁰CON(R²⁰)₂, CO₂R²⁰,CON(R²⁰)₂, and wherein each optional alkyl, and aryl substituent isoptionally substituted with halo, aLkyl, CF₃, CO₂R²⁰, S(O)₃R²⁰, CN, orOR²⁰; R⁶ is selected from the group consisting of H, and C₁-C₃ alkyl;and R′ is selected from the group consisting of H, and C₁-C₃ alkyl,wherein R⁶ and R⁸ may bond to form a 4 or 5 or 6 membered saturated orunsaturated ring. In the compositions above, R³ and R⁴ are each morepreferably hydrogen, R⁵ is more preferably C₁₋₈ alkyl such and methyl orcyclopentyl, and R⁸ is more preferably hydrogen.

[0033] In the compositions of this invention, R¹ is preferably mono orpolysubstituted with one or more compounds selected from the groupconsisting of halogen, oxo, hydroxyl, lower alkyl, substituted loweralkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl,heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, nitro, cyano and mixtures thereof. More preferably, RI is amonocyclic, bicyclic, or tricyclic cycloalkyl group containing from 3 to15 carbon atoms wherein at least one carbon atom is substituted with anatom or molecule selected from the group consisting of 0 or S—(O)₀₋₂.Some examples of preferred R¹ moieties include

[0034] wherein R₁′, R₁″, R₁′″, and R₁″″ may each individually beselected from the group Axhalogen, hydroxyl, lower alkyl, substitutedlower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl,heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, nitro, and cyano, and X is O, or S(—O)₀₋₂, alternately, R₁′″and R₁″″ may be a single oxygen atom. More preferably, R₁′, R₁″, R₁′″,and R₁″″ are each individually selected from the group hydrogen, loweralkyl, and substituted lower alkyl. In the compositions above, each R isindividually selected from the group consisting of H, lower alkyl, andsubstituted lower alkyl and wherein X is O, or S (—O)₀₋₂. R₁ is morepreferably selected from the group consisting of 3-tetrahydrofuranyl,3-tetrahydrothiofuranyl, 4-pyranyl, and 4 thiopyranyl. R₁ is mostpreferably 3-tetrahydrofuranyl.

[0035] Most preferred compounds of this invention include,(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-methyl carboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-ethylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-propylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-butylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-benzylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(4-fluorophenyl)methyl]carboxamide;{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclohexylcarboxamide;{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-(methylethyl)carboxamide;{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopropylcarboxamide;Methyl 2-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylate;Ethyl3-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-1:5syl)methoxy]carbonylamino}(2S,3R)bicylo[2.2.1]hept-5-ene-2-carboxylate;Ethyl 3-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3 ,4dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicylo[2.2. 1]heptane-2-carboxylate;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(IR,2R)-2-(phenyhnethoxy)cyclopentyl]carboxamide;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-2Qyl}(3S,²R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(1S,2S)-2-(phenylmethoxy)cyclopentyl]carboxamide;(5-{6-[((3R)oxolan-3-yl)amiino}purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-ylmethoxy]-N-cyclobutylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino}purin-9-yl}(³S,²R,4R,5R)-3,44ihydroxyoxolan-2-yl)methoxy]-N-(2-phenylcyclopropyl)carboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S, 2R, 4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-prop-2-enylcarboxamide; Ethyl3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolane-2-yl)methoxy}carbonylamino}propanoate;Methyl 2-{[(5-{6-[((3R)oxolan-3-yl)anino]purin-9-yl}(3S,²R,⁴R,5R)-3,4dihydroxyoxolane-2-yl)methoxy}carbonylamino}acetate;{(5-{6-[((3R)oxolan-3-yl)amnino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N,N-dimnethylcarboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(methylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(ethylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(methylethyl)amino]thioxomethoxy}methyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(butylamino)thioxomethoxy]methyl}oxolane-3 ,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(propylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-[(piperidylthioxomethoxy)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(cyclopentylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-[(pyrrolidinylthioxomethoxy)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(dimethylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[benzylamino]thioxomethoxy}methyl)oxolane-3,4-ysdiol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[cyclohexylamino]thioxometloxy}metlyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amnino]purin-9-yl}(4S,2R,3R,5R)-5-[({[(1S,2S)-2-(phenylmethoxy)cyclopentyl]amino}thioxomethoxy)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amnino]purin-9-yl}(4S,2R,3R,5R)-5-[({[(IR,2R)-2-(phenylmethoxy)cyclopentyl]amino}thioxomethoxy)methyl]oxolane-3,4-diol;2-{6-[((3)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,SR)-5-{[(cyclobutylamino)thioxomethoxy]methyl}oxolane-3,4&iol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(cyclopropylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(prop-2-enylamino)thioxomethoxy]methyl}oxolane-3,4-diol;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-((1S,2S)-2-hydroxycyclopentyl)carboxamide;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-((lR,2R)-2-hydroxycyclopentyl)carboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,SR)-5-({[((1R,2R)-2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[((1S,2S)-2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane-3,4-diol;2-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylicacid;3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid;3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}propanoicacid;2-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}aceticacid,5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2R,3R,4R,5R)-4-acetyloxy-2-[(N-methylcarbamoyloxy)methyl]oxolan-3-ylacetate;[(5-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-methylcarboxamide,[(5-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide;N-[(5-{6-[((3R)oxolan-3-yl)amnino]purin-9-yl}(3S,2R,4R,SR)-3,4-dihydroxyoxolan-2-yl)methyl]methoxycarboxamide;N-[(5-{6-[((3R)oxolan-3-yl)aniino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methy]cyclopentyloxycarboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[methoxythioxomethyl)amino]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[cyclopentyloxythioxomethyl)amino]methyl}oxolane-3,4-diol;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4&hydroxyoxolan-2-yl)methythio]-N-methylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methythio]-N-cyclopentylcarboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-{[(methylamino)thioxomethylthio]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-{[(cyclopentylamino)thioxomethylthio]methyl}oxolane-3,4-diol;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](methylamino)carboxamide;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](cyclopentylamino)carboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(methylamino)thioxomethyl]amino}methyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(cyclopentylamino)thioxomethyl]amino}methyl)oxolane-3 ,4-diol;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](ethylamino)carboxamide; and3-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R)-3,4-dihydroxyoxolan-2-yl)methyl]-1,3-oxazolin-2-one.

[0036] The following definitions apply to terms as used herein. “Halo”or “Halogen”—alone or in combination means all halogens, that is, chloro(Cl), fluoro (F), bromo (Br), iodo (I).

[0037] “Hydroxyl” refers to the group —OH.

[0038] “Thior” or “mercapto” refers to the group —SH.

[0039] “Alkyl”—alone or in combination means an alkane-derived radicalcontaining from 1 to 20, preferably 1 to 15 carbon atoms (unlessspecifically defined). It is a straight chain alkyl, branched alkyl orcycloalkyl. Preferably, straight or branched alkyl groups containingfrom 1-15, more preferably 1 to 8, even more preferably 1-6, yet morepreferably 1-4 and most preferably 1-2, carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term “loweralkyl” is used herein to describe the straight chain alkyl groupsdescribed immediately above. Preferably, cycloalkyl groups aremonocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably3-6, ring members per ring, such as -cyclopropyl, cyclopentyl,cyclohexyl, adamantyl and the like. Alkyl also includes a straight Uochain or branched alkyl group that contains or is interrupted by acycloaLkyl portion. The straight chain or branched aLkyl group isattached at any available point to produce a stable compound. Examplesof this include, but are not limited to, 4(isopropyl)-cyclohexylethyl or2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chainalkyl, branched alkyl, or cycloalkyl group defined previously,independently substituted with 1 to 3 groups or substituents of halo,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy,aryloxy, heteroaryloxy, amino optionally mono- or di-substituted withaikyl, aryl or heteroaryl groups, amidino, urea optionally substitutedwith alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyloptionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroarylgroups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

[0040] “Alkenyl”—alone or in combination means a straight, branched, orcyclic hydrocarbon containing 2-20, preferably 2-17, more preferably2-10, even more preferably 2-8, most preferably 2-4, carbon atoms and atleast one, preferably 1-3, more preferably 1-2, most preferably one,carbon to carbon double bond. In the case of a cycloalkyl group,conjugation of more than one carbon to carbon double bond is not such asto confer aromaticity to the ring. Carbon to carbon double bonds may beeither contained within a cycloalkyl portion, with the exception ofcyclopropyl, or within a straight chain or branched portion. Examples ofalkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl isthe straight chain alkenyl, branched alkenyl or cycloalkenyl groupdefined previously, independently substituted with 1 to 3 groups orsubstituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, or the like attached at any available point toproduce a stable compound.

[0041] “Alkynyl”—alone or in combination means a straight or branchedhydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, evenmore preferably 2-8, most preferably 2-4, carbon atoms containing atleast one, preferably one, carbon to carbon triple bond. Examples ofalkynyl groups include ethynyl, propynyl, butynyl and the like. Asubstituted alkynyl refers to the straight chain alkynyl or branchedalkenyl defined previously, independently substituted with 1 to 3 groupsor substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylarnino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylarnino, or the like attached at any available point toproduce a stable compound.

[0042] “Alkyl alkenyl” refers to a group —R—CR′═CR′″ R″″, where R islower alkyl, or substituted lower alkyl, R′, R′″, R″″ may independentlybe hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl,substituted aryl, hetaryl, or substituted hetaryl as defined below.

[0043] “Alkyl alkynyl” refers to a groups —RC═CR′ where R is lower alkylor substituted lower alkyl, R′ is hydrogen, lower alkyl, substitutedlower alkyl, acyl, aryl, substituted aryl, hetaryl, or substitutedhetaryl as defined below.

[0044] “Alkoxy” denotes the group —OR, where R is lower alkyl,substituted lower alkyl, acyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroalkyl, heteroarylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, or substitutedcycloheteroalkyl as defined.

[0045] “Alkylthio” denotes the group —SR, —S(O)_(n=1-2)—R, where R islower alkyl, substituted fi lower alkyl, aryl, substituted aryl, aralkylor substituted aralkyl as defined herein.

[0046] “Acyl” denotes groups —C(O)R, where R is hydrogen, lower alkylsubstituted lower allkyl, aryl, substituted aryl and the like as definedherein.

[0047] “Aryloxy” denotes groups —OAr, where Ar is an aryl, substitutedaryl, heteroaryl, or substituted heteroaryl group as defined herein.

[0048] “Amino” denotes the group NRR′, where R and R′ may independentlyby hydrogen, lower alkyl, substituted lower alkyl, aryl, substitutedaryl, hetaryl, or substituted hetaryl as defined herein or acyl.

[0049] “Amido” denotes the group —C(O)NRR′, where R and R′ mayindependently by hydrogen, lower alkyl, substituted lower alkyl, aryl,substituted aryl, hetaryl, substituted hetaryl as defined herein.

[0050] “Carboxyl” denotes the group —C(O)OR, where R is hydrogen, loweralkyl, substituted lower alkyl, aryl, substituted aryl, hetaryl, andsubstituted hetaryl as defined herein.

[0051] “Aryl”—alone or in combination means phenyl or naphthyloptionally carbocyclic fuised with a cycloalkyl of preferably 5-7, morepreferably 5-6, ring members and/or optionally substituted with 1 to 3groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

[0052] “Substituted aryl” refers to aryl optionally substituted with oneor more functional groups, e.g., halogen, lower alkyl, lower alkoxy,alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy,heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfarnido and the like.

[0053] “Heterocycle” refers to a saturated, unsaturated, or aromaticcarbocyclic group having a single ring (e.g., morpholino, pyridyl orfuryl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl,quinolinyl, indolizinyl or benzo[b]thienyl) and having at least onehetero atom, such as N, O or S, within the ring, which can optionally beunsubstituted or i$ substituted with, e.g., halogen, lower alkyl, loweralkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl,aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0054] “Heteroaryl”—alone or in combination means a monocyclic aromaticring structure containing 5 or 6 ring atoms, or a bicyclic aromaticgroup having 8 to 10 atoms, containing one or more, preferably 14, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group O, S, and N, and optionally substituted with 1to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable aromatic ring is retained. Examples ofheteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazinyl, furanyl, benzoftiryl, indolyl and thelike. A substituted heteroaryl contains a substituent attached at anavailable carbon or nitrogen to produce a stable compound.

[0055] “Heterocyclyl”—alone or in combination means a non-aromaticcycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbonatoms in the ring are replaced by heteroatoms of O, S or N, and areoptionally benzo fused or fiused heteroaryl of 5-6 ring members and/orare optionally substituted as in the case of cycloalkyl. Heterocycyl isalso intended to include oxidized S or N, such as sulfinyl, sulfonyl andN-oxide of a tertiary ring nitrogen. The point of attachment is at acarbon or nitrogen atom. Examples of heterocyclyl groups aretetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl,piperazinyl, dihydrobenzofuryl, dihydroindolyl, and the like. Asubstituted hetercyclyl contains a substituent nitrogen attached at anavailable carbon or nitrogen to produce a stable compound.

[0056] “Substituted heteroaryl” refers to a heterocycle optionally monoor poly substituted with one or more functional groups, e.g., halogen,lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0057] “Aralkyl” refers to the group —R—Ar where Ar is an aryl group andR is lower alkyl or substituted lower alkyl group. Aryl groups canoptionally be unsubstituted or substituted with, e.g., halogen, loweralkyl, alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl,aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0058] “HeteroaLkyl” refers to the group —R—Het where Het is aheterocycle group and R is a lower alkyl group. Heteroalkyl groups canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl,aryloxy, heterocycle, substituted heterocycle, hetaryl, substitutedhetaryl, nitro, cyano, thiol, sulfamido and the like.

[0059] “Heteroarylalkyl” refers to the group —R—HetAr where HetAr is anheteroaryl group and R lower alkyl or substituted lower alkyl.Heteroarylalkyl groups can optionally be unsubstituted or substitutedwith, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy,alkylthio, acetylene, aryl, aryloxy, heterocycle, substitutedheterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0060] “Cycloalkyl” refers to a divalent cyclic or polycyclic alkylgroup containing 3 to 15 carbon atoms.

[0061] “Substituted cycloalkyl” refers to a cycloalkyl group comprisingone or more substituents with, e.g., halogen, lower alkyl, substitutedlower alkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

[0062] “Cycloheteroalkyl” refers to a cycloalkyl group wherein one ormore of the ring carbon atoms is replaced with a heteroatom (e.g., N, O,S or P).

[0063] “Substituted cycloheteroalkyl” refers to a cycloheteroalkyl groupas herein defined which contains one or more substituents, such ashalogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido,carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substituted tsheterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

[0064] “Alkyl cycloalkyl” denotes the group —R-cycloalkyl wherecycloalkyl is a cycloalkyl group and R is a lower alkyl or substitutedlower alkyl. Cycloalkyl groups can optionally be unsubstituted orsubstituted with e.g. halogen, lower alkyl, lower alkoxy, alkylthio,acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, o substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

[0065] “Alkyl cycloheteroalkyl” denotes the group —R-cycloheteroalkylwhere R is a lower alkyl or substituted lower alkyl. Cycloheteroalkylgroups can optionally be unsubstituted or substituted with e.g. halogen,lower alkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

[0066] The compounds of this invention can be prepared as outlined inthe schemes 1-10, below. The primary amino compound, R₁NH₂, is eithercommercially available or can be prepared as previously described (U.S.Pat. No. 5,789,416).Compound I can be prepared, following the proceduresreported earlier (U.S. Pat. No. 5,789,416, the specification of which isincorporated herein by reference), by reacting 6-chloropurine riboside 1with a primary amine R¹NH₂. To facilitate carbamate formation at the 5′position, 2′, 3′ hydroxy groups can be protected as acetonide by reatingI with 2,2′-dimethoxypropane in the presence of catalytic amount of TsOH[Evans, Parrish and Long Carbohydrat. Res., 3, 453 (1967)] to give II.Reaction of II with CDI or thio-CDI followed by treatment with an aminewith the general formula R⁵R⁸NH can give carbamates with general formulaIII. Treatment of III with an acid can free the 2′, 3′ positions to givecarbamates with general formula IV. Esterification at the 2′, 3′positions can afford 2′, 3′ diesters with the general formula V.

[0067] The 2-substituted derivatives with the general formula XIII canbe prepared as shown in scheme 2. Condensation of1,2,3,5-tetraacetylribofiuranoside 2 with 2-substituted 6-chloropurineVI can give 2-substituted-6-chloropurineriboside triacetate VII which onreaction with a primary amine R¹NH₂ can give 2-substituted-6-alkylarninoderivatives VIII. Hydrolysis of the acetates followed by protection ofthe 2′, 3′ hydroxy groups as an acetonide can give X. Reaction of X witheither CDI or thio CDI followed by reaction with an amine R⁵R⁸NH₂ cangive carbarnate or thionocarbarnate with the general

[0068] formula XI. Deprotection of the 2′, 3′-positions can givecarbarnates with the general formula XII. Esterification of the 2′, 3′hydroxyls can give diesters with the general formula XIII.

[0069] Preparation of compounds 6 and 7 starting from compound 3 isshown in Scheme 3. Compound 3 was prepared from 6-chloropurineriboside 1and 3 (R)-aminotetrahydrofaran following the procedure reported earlier(U.S. Pat. No. 5,789,416). Protection of the 2′ and 3′ hydroxy groups asan acetonide with 2,2-dimethoxypropane in the presence of TsOH(cat.)gave 4. Reaction of 4 with CDI in THF followed by treatment with 40%aq.methylamine gave carbamate 5. Deprotection of the 2′,3′ acetonidewith 80% AcOH/water at 80-90 C gave carbamate 6. Esterification of 6with acetic anhydride in pyridine gave diester 7.

[0070] Preparation of compound 13 starting from compound 2 is shown inscheme 4. Compound 8 was prepared following the previously describedprocedure (John A. Montgomery et.al. J. Heterocycl. Chem. 1964, 213.).Selective displacement of the 6-chloro with 3 (R)-aminotetrahydrofuranfollowing the procedure reported earlier (U.S. Pat. No. 5,789,416, thespecification of which is incorporated herein by reference) gave 9.Hydrolysis of the acetates at the 2′, 3′, 5′ positions with aq. ammoniagave trihydroxy compound 10. Protection of the 2′ and 3′ hydroxy groupsas an acetonide with 2,2-dimethoxypropane in the presence of TsOH(cat.)gave 11. Reaction of 11

[0071] with CDI in TBF followed by treatment with 40% aq.methylaminegave carbamate 12. Deprotection of 12 with 80% AcOH/water at 80-90° C.gave carbamate 13.

[0072] Carbamates with general structure XVIII can be prepared from thekey intermediate compound XVI as shown in Scheme 5.

[0073] Compound XVI can be prepared by the reduction of compound XVusing 10% Pd—C and hydrogen (J. March, Advanced Organic Chemistry,4^(th) edition, p 1220). Compound XV can be prepared by the nucleophilicdisplacement of the corresponding mesylate (XV) with sodium azide (J.March, Advanced Organic Chemistry, 4^(th) edition, p 428) which can beprepared from the alcohol by treating compound II with methanesulfonylchloride in pyridine.

[0074] 5′-Thiocarbamates represented by the general structure XXII canbe prepared as shown in Scheme 6.

[0075] The key intermediate XX can be prepared by the deacylation ofcompound XIX that can be prepared by the nucleophilic displacement ofthe mesylate (XIV) by potassium thioacetate. Compound XNI can beobtained by the reaction of XX with isocyanates or isothiocyanates inacetonitrile, DMAP, followed by deprotection of the acetonide usingaqueous acetic acid.

[0076] The ureas and thioureas represented by the general formula XXVcan be prepared from compound XVI, as shown in Scheme 7, by reactingwith an isocyanate or isothiocyanate in acetonitrile, DMAP, followed bydeprotection using aqueous acetic acid. Compound XVI can be prepared asdescribed before (Scheme 5).

[0077] Synthesis of compound 18 was carried out as shown in Scheme 8.Compound 4 was synthesized as described before (Scheme 3). Compound 14was prepared by the reaction of 4 with methanesulfonyl chloride inpyridine at 0° C. Reaction of 14 with sodium azide in DMF at 65° C. gavethe compound 15. Reduction of the azide 15 with hydrogen and 10% Pd—Cgave the corresponding 5′-amino compound 16. Reaction of the amine 16with methyl imidazole carboxylate in THF at room temperature followed bydeprotection using aqueous acetic acid gave compound 18.

[0078] Compound 22 was synthesized as shown in Scheme 9. The mesylate 15was prepared as described before (Scheme 8). Reaction of 15 withpotassium thioacetate in THF at room temperature gave compound 19.Hydrolysis of compound 19 with sodium methoxide in methanol gave thethiol 20. Reaction of 20 with methyl isocyanate in acetonitrile and DMAPfollowed by deprotection gave compound 22.

[0079] Compound 24 was prepared (Scheme 10) by the reaction of compound16 with methyl isocyanate in acetonitrile, DMAP at room temperaturefollowed by deprotection with aqueous acetyic acid. Compound 16 wassynthesized as described before (Scheme 8).

[0080] This invention also includes pro-drugs of the A₁ agonistcompositions of this invention. A pro-drug is a drug which has beenchemically modified and may be biologically inactive at its site ofaction, but which will be degraded or modified by one or more enzymaticor in vivo processes to the bioactive form. The pro-drugs of thisinvention should have a different pharmacokinetic profile to the parentenabling improved absorption across the mucosal epithelium, better saltformulation and/or solubility and improved systemic stability. Thecompounds of this invention may be preferably modified at one or more ofthe hydroxyl groups to form pro-drugs. The modifications may be (1)ester derivatives which may be cleaved by esterases or lipases, forexample. The pro-drug esters of this invention can be prepared using allof the known methods for ester formation which are included by reference(see Jerry March Organic synthesis and Richard Larock—Methods of OrganicSynthesis), and more preferably by those outlined in this application;(2) peptides which may be recognized by specific or non specificproteinase; or (3) derivatives that accumulate at a site of actionthrough membrane selection or a pro-drug form or modified pro-drug form,or any combination of (1) to (3) above.

[0081] If a compound of this invention contains a basic group, thencorresponding acid addition salt may be prepared. Acid addition salts ofthe compounds are prepared in a standard manner in a suitable solventfrom the parent compound and an excess of acid, such as hydrochloric,hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic, ormethanesulfonic. The hydrochloric salt form is especially useful. If acompound of this invention contains an acidic group, then correspondingcationic salts may be prepared. Typically the parent compound is treatedwith an excess of an alkaline reagent, such as hydroxide, carbonate oralkoxide, containing the appropriate cation. Cations such as Na⁺, K⁺,Ca⁺² and NH₄ ⁺ are examples of cations present in pharmaceuticallyacceptable salts. Certain of the compounds form inner salts orzwitterions which may also be acceptable.

[0082] The compositions of this invention are useful for treating avariety of mammalian disorders and preferably human disorders that aremediated by an A₁ adenosine receptor. For example, the compositions ofthis invention are useful for modifying cardiac activity in mammalsexperiencing a coronary electrical disorder that can be treated bystimulating an A₁ adenosine receptor. Examples of coronary electricaldisorders that can be treated by the compositions of this inventioninclude supraventricular tachycardias, atrial fibrillation, atrialflutter, and AV nodal re-entrant tachycardia. Furthermore, orally activeA, agonists of this invention that demonstrate an excellent safetyprofile in treating supraventricular arrhythmias may also be used as aprophylactic for those at high risk of a myocardial ischemia.

[0083] The compositions of this invention are also useful for modifiingadipocyte function by stimulating an A₁ adenosine receptor that leads todiminished release of NEFA and increased release of leptin. Diseasestates related to adipocyte function that can be modified usingcompositions of this invention include diabetes, and obesity.

[0084] In skeletal muscle cells, A₁ AdoR agonists mediate a synergisticstimulation of glucose uptake and transport by insulin (Vergauwen, L. etal, J. Clin. Invest. 1994, 93, 974-81; Challiss, R. A. et al,Eur.J.Pharacol., 1992, 226, 121-8). Another therapeutic utility ofcompositions of this invention is more efficient regulation of glucosedecrease in insulin in patients afflicted with diabetes.

[0085] The A₁ receptor agonist, R-PIA, has been shown to increase theleptin released from white adipocytes and augment insulin-stimulatedleptin production (M. Ozeck Master's Thesis Univ. of Florida 1999 withL. Belardinelli). Evidence suggests that catecholamines inhibit theproduction of leptin from adipocytes through activation of β-adrenergicreceptors. The anti-β-adrenergic effects of A₁ agonists on theadipocytes are believed to play a role in the increased release ofleptin. The functional role of leptin is multifaceted includingdecreased appetite, stimulated energy utilization, and increasedfertility.

[0086] The compositions of this invention may also be used to providecentral nervous system neuroprotection by stimulating an A₁ adenosinereceptor. Central nervous system disorders that may be treated using thecompositions of this invention include epilepsy, and stroke.

[0087] In the kidney, there is evidence that stimulation of the A, AdoRpromotes sodium retention, promotes exchange of sodium in urine forpotassium, and reduces glomerular filtration rate as sodium excretionincreases (Gellai, M. et al, JPET, 1998, 286, 1191-6; Wilcox, C. S. etal, J.Am.Soc.Nephrol., 1999, 10, 714-720). It is believed that theseresponses are elicited by chronic local production of adenosine. Thatis, in the kidney there is a tonic effect of adenosine to stimulate theA₁ AdoR. Another clinical utility of compositions of this invention,therefore, is the selective antagonism of the A₁ AdoR in the kidney toinhibit sodium retention, inhibit the exchange of sodium for potassium,and preserve kidney glomerular filtration rate when sodium excretionrises to yield a potassium sparring diuretic that preserves renalfunction.

[0088] The compositions of this invention are further useful forproviding cardiomyocyte protection from ischemic events by stimulatingan A₁ adenosine receptor. Ischemic events treatable using thecompositions of this invention include stable angina, unstable angina,cardiac transplant, and myocardial infarction.

[0089] An important aspect of compounds of this invention is that eachcompound has an intrinsic efficacy associated with it (for a discussionsee T. P. Kenakin Stimulus Response Mechanisms. In PharmacologicalAnalysis of Drug-Receptor Interaction, Ed. Kenakin, T. P. New York:Raven Press, p 39-68). This intrinsic efficacy is not defined by it'saffinity for the receptor, but it is defined as the quantitative effectof the compound to activate a given effector system (eg. cAMPproduction) in a given cell type. The intrinsic efficacy of a givencompound may vary from cell type to cell type and/or from effectorsystem to effector system. When a compound has an intrinsic efficacylower than a fuill agonist (i.e. submaximal) than the agonist is calleda partial agonist. Thus, a partial agonist is a molecule that binds to areceptor and elicits a response that is smaller than that of a fullagonist (submaximal), but also competitively antagonizes the response(s)elicited by a full agonist (e.g., adenosine). The tonic action ofadenosine with respect to kidney function is a prime example wherein apartial A₁ agonist could be expected to act as an antagonist. Thecompounds of this invention are believed to have therapeutically usefulaffinities for the adenosine Al receptor, and they will have a range ofintrinsic efficacies from full agonist to partial agonist. That is, somecompounds may have no effect with respect to a given effector system ina given cell type, but be a full agonist in another cell type and/oreffector system. The reason for such variable pharmacological behaviorrelates to the magnitude of the receptor reserve for the A₁ adenosinereceptor in any given cell type (eg. AV nodal cells vs. adipocytes) andfor a given response. The receptor reserve (spare receptor capacity) isthe total number of receptors minus the fraction of receptors that isrequired to induce the maximal response using a fuill agonist (L. E.Limbird, Cell Surface Receptors: A Short Course on Theory and Methods,Kluwer Acad. Pub. 1996, Boston, Mass.). Therefore, the agonist could bea full agonist at eliciting a response, and a partial agonist foreliciting another response in other tissue or cells and still be anantagonist or lack activity for a third response in another tissue orcell. Consequently, a partial agonist targeted to a selected target islikely to cause fewer side effects than a full agonist. As a corollary,a full agonist elicits all the effects mediated by the respectivereceptor, whereas this is not necessarily the case of a partial agonist.The compounds of this invention based on their affinity for the A₁receptor and their potency and selectivity to elicit A₁ receptormediated responses have the potential for therapeutic intervention inthe multiple disease states described above.

[0090] Partial A₁ agonists may have an added benefit for chronic therapybecause they will be less likely to induce desensitization of the A₁receptor (R. B. Clark, B. J. Knoll, R. Barber TIPS, Vol. 20 (1999) p.279-286) and to cause side effects. Chronic administration of a fullagonist (R-N6-phenylisopropyladenosine, R-PIA) for 7 days led to adesensitization of the Al b receptor in terms of the dromotropicresponse in guinea pigs (note: a decrease in receptor number wasobserved—D. M. Dennis, J. C. Shryock, L. Belardinelli JPET, Vol. 272(1995) p. 1024-1035). The A₁ agonist induced inhibitory effect on theproduction of cAMP by adenylate cyclase in adipocytes has been shown todesensitize upon chronic treatment with an A₁ agonist as well (W. J.Parsons and G. L. Stiles J. Biol. Chem. Vol. 262 (1987) p. 841-847).

[0091] The compositions of this invention may be administered orally,intravenously, through the epidermis, bolus, nasally, by inhalation orby any other means known in the art for administering a therapeuticagents. The method of treatment comprises the administration of aneffective quantity of the chosen compound, preferably dispersed in apharmaceutical carrier. Dosage units of the active ingredient aregenerally selected from the range of 0.01 to 100 mg/kg, but will bereadily determined by one skilled in the art depending upon the route ofadministration, age and condition of the patient.

[0092] Pharmaceutical compositions including the compounds of thisinvention, and/or derivatives thereof, may be formulated as solutions orlyophilized powders for parenteral administration. Powders may bereconstituted by addition of a suitable diluent or otherpharmaceutically acceptable carrier prior to use. If used in liquid formthe compositions of this invention are preferably incorporated into abuffered, isotonic, aqueous solution. Examples of suitable diluents arenormal isotonic saline solution, standard 5% dextrose in water andbuffered sodium or ammonium acetate solution. Such liquid formulationsare suitable for parenteral administration, but may also be used fororal administration. It may be desirable to add excipients such aspolyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethyleneglycol, mannitol, sodium chloride, sodium citrate or any other excipientknown to one of skill in the art to pharmaceutical compositionsincluding compounds of this invention. Alternatively, the pharmaceuticalcompounds may be encapsulated, tableted or prepared in an emulsion orsyrup for oral administration. Pharmaceutically acceptable solid orliquid carriers may be added to enhance or stabilize the composition, orto facilitate preparation of the composition. Liquid carriers includesyrup, peanut oil, olive oil, glycerin, saline, alcohols and water.Solid carriers include starch, lactose, calcium sulfate, dihydrate,teffa alba, magnesium stearate or stearic acid, talc, pectin, acacia,agar or gelatin. The carrier may also include a sustained releasematerial such as glycerol monostearate or glycerol distearate, alone orwith a wax. The amount of solid carrier varies but, preferably, will bebetween about 20 mg to about 1 gram per dosage unit. The pharmaceuticaldosages are made using conventional techniques such as milling, mixing,granulation, and compressing, when necessary, for tablet forms; ormilling, mixing and filling for hard gelatin capsule forms. When aliquid carrier is used, the preparation will be in the form of a syrup,elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquidformulation may be administered directly or filled into a soft gelatincapsule.

[0093] The Examples which follow serve to illustrate this invention. TheExamples are intended to in no way limit the scope of this invention,but are provided to show how to make and use the compounds of thisinvention.

EXAMPLE 1

[0094]

[0095] Intermediate—(4-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(1R, 2R,5R)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)methan-1-ol (15A)

[0096] To a solution of compound 1 (2.0 g, 6.0 mmol) and2,2-dimethoxypropane (1.2 g, 11.8 mmol) in dimethylformamide (20 mL) wasadded p-toluenesulfonic acid (50 mg, 0.26 -nmmol) at 70° C. After 48 hat 70° C., the reaction was concentrated in vacuo to afford a solid. mThe solid was dissolved in methanol (3 mL), then triturated with ethylether (50 mL). The resultant crystals were collected by vacuumfiltration to afford the intermediate 4.

[0097]Intermediate-[(4-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)methoxy]-N-methylcarboxamide(5)

[0098] To a solution of compound 4 (190 mg, 0.5 mmol) in THF (1 mL) wasadded carbonyldiimidazole (324 mg, 2 mmol) at rt. After stirring for 2 h, excess reagent was quenched by adding a drop of water. Methylamine(40% aq. Solution, 1 mL) was added and stirring was continued foranother 16h. The reaction mixture was concentrated in vacuo to afford agum. It was purified by prep.TLC [(silica gel, 10%MeOH-dichloromethane)] to afford compound 5 (100ng).

[0099](5-16[((3R)oxolan-3-yl)aminolpurin-9-yl)(3S,2R,4R,5R)-3,4dihydroxyoxolan-2yl)methoxyl-N-methylearboxamide.(6)

[0100] Compound 5 (100 mg) was taken in a mixture of acetic acid (16 mL)and water (4 mL) and heated at 90 C for 16 h. Solvents were removedunder reduced pressure and the residue was purified by preparative TLC[methanol-dichloromethane (1:9)] to afford compound 6. ¹H NMR(CD₃OD)1.95-2.05 (m, 1H), 2.30-2.40 (m, 1H), 2.70 (s, 3H), 3.75-3.80 (m, 1H),3.82-3.90 (m, 1H), 3.95-4.10 (m, 2H), 4.20-4.45 (m, 4H), 4.65 (t, 1H),4.70-4.90 (m, 1H), 6.00 (d, 1H), 8.20 (s, 1H), 8.25 (s, 1H).

[0101][(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-ethylcarboxamide(25)

[0102] This compound was prepared in a manner similar to that of 6,substituting ethyl amine for methyl amine: (M+1)=409.35

[0103][(5-{1[((3R)oxolan-3-yl)aminolpurin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2-yl)methoxyl-N-propylcarboxamide(26)

[0104] This compound was prepared in a manner similar to that of 6,substituting propyl amine for methyl amine: (M+1)=423.35

[0105][(5-{6-[((3R)oxolan-3yl)aininolpurin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2yl)methoxyl-N-butylcarboxamiide(27)

[0106] This compound was prepared in a marimer similar to that of 6,substituting n-butyl amine for methyl amine: (M+1)=437.39

[0107][(5-{6-[((3R)oxolan-3yl)aminolpurin-9-yl}(3S,2R,4R,5R)3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide(28)

[0108] This compound was prepared in a manner similar to that of 6,substituting cyclopentyl amine for methyl amine: (M+1)=449.38

[0109][(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2-yl)methoxy]-N-benzylcarboxamide(29)

[0110] This compound was prepared in a manner similar to that of 6,substituting benzyl amine for methyl amine: (M+1)=471.37

[0111][(5-{6[((3R)oxolan-3-yl)aniiiiolpurin-9-yl}(3S,2R,4R,5R)3,4dihydroxyoxolan-2-yl)methoxy]-N-[(4fluorophenyl)methyllcarboxamide(30)

[0112] This compound was prepared in a manner similar to that of 6,substituting 4-fluorobenzyl amine for methyl amine: (M+1)=489.3

[0113]{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclohexylcarboxamide(31)

[0114] This compound was prepared in a manner similar to that of 6,substituting cyclohexyl amine for methyl amine: ¹ H NMR (CD₃OD) 1.1-1.95(m, 11H), 2.35 (m, 1H), 3.75-4.55 (m, 11H), 5.98 (d, 1H), 8.12 (s, 1H),8.25 (s, 1H).

[0115]{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R3,4-dihydroxyoxolan-2-yI)methoxy]-N-(methylethyl)carboxamide(32)This compound was prepared in a manner similar to that of 6,substituting i-propyl amine for methyl amine: (M+1)=423.3

[0116]{(5-{6[((3R)oxolan-3-yl)aminolpurin-9-yl}(3S,2R,4R,5R)3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopropylcarboxamide(33)

[0117] This compound was prepared in a manner similar to that of 6,substituting cyclopropyl amine for methyl amine: 1H NMR (CDCl₃) 0.45 (m,2H), 0.69 (m, 2H), 1.95 (m, 1H), 2.38 (m, 1H), 22.51 (m, 1H), 3.82-4.85(m, 10H), 5.94 (d, 1H), 7.95 (s, 1H), 8.25 (s, 1H)].

[0118] Methyl2-{[5-{6-[(3R)oxolan-3-yl)aminolpurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylate(34)

[0119] This compound was prepared in a manner similar to that of 6,substituting 2-carbomethoxy cyclopentyl amine for methyl amine:(m+1)=507.31

[0120] Ethyl3-{[5-{6-[(3R)oxolan-3-yl)amiinolpurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxylcarbonylamino)(2S,3R)bicylo[2.2.]hept-5-ene2-carboxylate(35)

[0121] This compound was prepared in a manner similar to that of 6,substituting 2 aboethoxy norbomn-5-enyl-2-amine for methyl amine: (M+1)=545.32

[0122] Ethyl3-{[5-{6-[(3R)oxolan-3-yl)aminolpurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxylcarbonylamino}(2S,3R)bicylo[2.2.1 ]heptane-2-carboxylate(36)

[0123] This compound was prepared in a manner similar to that of 6,substituting 3-carboethoxy norbom-5-yl-2-amine for methyl amine:(M+1)=547.38

[0124]{(5-{6[((3R)oxolan-3-yl)amino[purin-9-yl}(3S,2R,4R,5R)3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(1R,2R)-2-(phenylmethoxy)cyclopentyl]carboxamide(37)

[0125] This compound was prepared in a manner similar to that of 6,substituting (1R,2R)-2-benzyloxycyclopentyl amine for methyl amine:(M+1)=555.50

[0126]{(5-{6[((3R)oxolan-3-yl)aminolpurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxyl-N-[(1 S,2S)-2-(phenylmethoxy)cyclopentyl] carboxamide(38)

[0127] This compound was prepared in a manner similar to that of 6,substituting (1S,2S)-2-benzyloxycyclopentyl amine for methyl amine:(M+1)=555.50

[0128][(5-{6[((3R)oxolan-3-yl)amino}purin-9-yl}(3S,2R,4R,5R)3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclobutylcarboxaniide(39)

[0129] This compound was prepared in a manner similar to that of 6,substituting cyclobutyl amine for methyl amine: (M+1)=435.46.

[0130][(5-{6-[((3R)oxolan-3-yl)amino}purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-(2-phenylcyclopropyl)carboxamide(40)

[0131] This compound was prepared in a manner similar to that of 6,substituting 2-phenylcyclopropyl amine for methyl amine: (M+1)=497.50

[0132] [(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S, 2R, 4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-prop2-enylcarboxamide(41)

[0133] This compound was prepared in a manner similar to that of 6,substituting allyl amine for methyl amine: (M+1)=421.39

[0134] Ethyl 3-{[(5-{6-[((3R)oxolan-3-yl)aminolpurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolane2-yl)methoxy}carbonylamino}propanoate(42).

[0135] This compound was prepared in a manner similar to that of 6,substituting ethyl 3-aminopropionate for methyl amine: (M+1)=481.37

[0136] Methyl 2-{[(5-{6-[((3R)oxolan-3-yl)aminolpurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolane-2-yl)methoxy}carbonylamino}acetate(43)

[0137] This compound was prepared in a manner similar to that of 6,substituting methyl 2-aminoacetate for methyl amine: (M+1)=453.39

[0138]{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N,N-dimethylcarboxamide(44)

[0139] Compound 44 was prepared in a manner similar to compound 6substituting N,N-dimethyl amine for methyl amine ¹H NMR (CDCl₃): 1.95(m, 1H), 2.36 (m, 1H), 2.75 (s, 3H), 2.85 (s, 3H), 3.85-4.84 (m, 10H),5.95 (d, 1H), 7.95 (1H), 8.25 (s, 1H).

EXAMPLE 2

[0140]

[0141] 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5{1(methylamino)thioxomethoxyl methyl}oxolane3,4diol(45)

[0142] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI): (M+1)=411.30

[0143]2-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(ethylamino)thioxomethoxy]methyl}oxolane3,4diol(46)

[0144] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimnidazole(thioCDI) for carbonyldiimidazole(CDI) and ethyl amine for methyl amine: (M+1)=425.30

[0145]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5({[(methylethyl)amino]thioxomethoxy}methyl)oxolane3,4-diol(47)

[0146] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and i-propyl amine for methyl amine: (M+1)=439.30

[0147]2-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(butylamnino)thioxomethoxy]methylloxolane3,4-diol(48)

[0148] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and n-butyl amine for methyl amine: M+1)=453.30

[0149] 2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5{[(propylamino)thioxomethoxy]methyl}oxolane3,4-diol(49)

[0150] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and n-propyl amine for methyl amine: (M+1)=439.30

[0151]2-{6[((3R)oxolan-3-yl)amino]purin-9yl}(4S,2R,3R,5R)5[(piperidylthioxomethoxy)methylloxolane3,4diol(50)

[0152] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and piperidine for methyl amine: (M+1)=465.30

[0153]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5{[(cyclopentylamino)thioxomethoxy]methyl}oxolane3,4-diol(51)

[0154] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and cyclopentyl amine for methyl amine: (M+1)=465.30

[0155]2-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-l(pyrrolidinylthioxomethoxy)methyl]oxolane3,4diol(52)

[0156] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimnidazole(thioCDI) for carbonyldiimidazole(CDI) and pyrrolidine for methyl amine: (M+1)=451.30

[0157]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(dimethylamino)thioxomethoxy]methyl}oxolane-3,4-diol(53)

[0158] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and N,N-dimethyl amine for methyl amine: (M+1)=425.30

[0159]2-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({([benzylamino]thioxomethoxy}methyl)oxolane-3,4-diol(54)

[0160] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and benzyl amine for methyl amine: (M+1)=487.30

[0161]2-{6((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[cyclohexylamino]thioxomethoxy}methyl)oxolane-3,4-diol(55)

[0162] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and cyclohexyl amine for methyl amine: (M+1)=479.30

[0163]2-{6[((3R)oxolan-3-yl)amino]purin-9-yl)(4S,2R,3R,5R)5-[(([(1S,2S)-2-(phenylmethoxy)cyclopentyl]aminothioxomethoxy)methylloxolane3,4-diol(56)

[0164] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and (1S,2S)-2-benzyloxycyclopentyl amine for methylamine: (M+1)=571.47

[0165]2-{6-[((3R)oxolan-3-yl)amnino]purin-9-yl}(4S,2R,3R,5R)-5-[({[1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}thioxomethoxy)methyl]oxolane3,4diol(57)

[0166] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and (1R,2R)-2-benzyloxycyelopentyl amine for methylamine: (M+1)=571.47

[0167]2-{1[((3)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(cyclobutylamino)thioxomethoxy]methyl}oxolane-3,4-diol(58)

[0168] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and cyclobutyl amine for methyl amine: (M+1)=451.44

[0169]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R5-{[(cyclopropylamino)thioxomethoxy]methyl}oxolane-3,4-diol(59)

[0170] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimnidazole(thioCDI) for carbonyldiimidazole(CDI) and cyclopropyl amine for methyl amnine: (M+1)=437.43.

[0171]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(prop-2-enylaminio)thioxomethoxy]methyl}oxolane3,4diol(60)

[0172] This compound was prepared in a manner similar to that of 6,substituting thiocarbonyl diimidazole(thioCDI) for carbonyldiimidazole(CDI) and allyl amine for methyl amine: (M+1)=43 7.43.

EXAMPLE 3

[0173]

[0174]{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2-yl)methoxy]-N-((1S,2S)-2-hydroxycyclopentyl)carboxamide(61)

[0175] Compound 38 (25mg), ethanol (5 mL), cyclohexene (5 mL), andpalladium hydroxide on carbon (50mg) were mixed and refluxed for 48h.The catalyst was filtered through celite by gravity filtration and thesolvent was removed under reduced pressure to give 61: (M+1)=465.29

[0176]{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2-yl)methoxy]-N-((1R,2R2-hydroxycyclopentyl)carboxamide(62)

[0177] This compound was prepared from 37 using the procedure similar tothat used for 61: (M+1)=465.29

[0178]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yi}(4S,2R,3R,5R)-5({[((1R,2R2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane-3,4diol(63)

[0179] This compound was prepared from 57 using the procedure similar tothat used for 61: (M+1)=465.29.

[0180]2-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R5({[((1S,2S)2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane3,4diol(64)

[0181] This compound was prepared from 56 using the procedure similar tothat used for 61: (M+1)=465.29.

EXAMPLE 4

[0182]

[0183]2-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R3,4dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylicacid (65)

[0184] To a cooled (0° C.) solution of ester 34 (12 mg) in 2:1 TBF:H2O(2 mL) was added 3eq. of lithium hydroxide monohydrate (2 M solution inwater). The reaction was allowed to stir at 0° C. for 2 hours, thenallowed to warm to room temperature for 30 minutes. After all the esterwas consumed as judged by TLC, amberlite resin (approximately 4mg) wasadded and the solution was filtered through a cotton plug. Evaporationof solvent gave the pure acid 65: (M+1)=493.33

[0185]3-{[(5-{1[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)3,4dihydroxyoxolan-2-yl)methoxy]carbonylanmino}(2S,3R)bicyclo[2.2.1]hept-5-ene-2-carboxylicacid (66)

[0186] This compound was prepared from compound 35 using the proceduresimilar to that used for 65: (m+1)32 517.35

[0187]3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R3,4-dihydroxyoxolan-2yl)methoxy]carbonylamino}propanoicacid(67)

[0188] This compound was prepared from compound 42 using the proceduresimilar to that used for 65: (m+1)=453.32

[0189]2-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}aceticacid(68)

[0190] This compound was prepared from compound 43 using the proceduresimilar to that used for 65: (m+1)=439.30

EXAMPLE 5

[0191]

[0192]5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2R,3R,4R,5R)4-acetyloxy-2-[(N-methylcarbamoyloxy)methyl]oxolan-3-ylacetate(7)

[0193] To a solution of compound 6 (70 mg) and dimethylaminopyridine (50mg) in pyridine (2 mL) at 23° C. was added acetic anhydride (0.1 mL).After 3 h at 23° C., the reaction was concentrated in vacuo . Theresidue was dissolved in methylene chloride (50 mL), washed with water(3×10 mL), and dried (Na₂SO₄). After concentration in vacuao, theresidue was purified by flash chromatography (methylene chloride:methanol 20:1 followed by 9:1) to afford compound 7(70 mg): ¹H NMR(CDCl₃) 1.95-2.00 (m, 1H), 2.02 (s, 3H), 2.05 (s, 3H), 2.15-2.25 (m,1H), 2.40 (s, 3H), 3.75-3.85 (m, 2H), 3.95-4.05 (m, 2H), 4.30-4.45 (m,3H), 4.80-4.95 (m, 1H), 5.40 (bs, 1H), 5.60-5.62(m, 1H), 5.80-5.82(m,1H), 6.206.02 (m, 1H), 6.80-6.90 (bs, 1H), 8.00 (s, 1H), 8.35 (s, 1H).

EXAMPLE 6

[0194]

[0195]2-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(4S,2R,3R,5R)-5-(hydroxymethyl)oxolane3,4-diol(10)

[0196] Compound 8 was prepared from 1,2,3,4-tetra-O-acetylribofuranoside2 and 2,6-dichloropurine following the procedure reported in theliterature (John A. Montgomery et.al. J. Heterocycl. Chem. 1964, 213.) Amixture of compound 8 (1.g, 2.24 mmol) and (R)-3-amino tetrahydrofuran(tosylate salt) (0.75 g, 3 mmol) in methanol were stirred for 16 h.Methanol was evaporated under reduced pressure and the residue wasfiltered through a plug of silica gel to give a gum. An NMR spectrum ofthis gum showed peaks corresponding to compound 9. This material wasused without fiwther purification in the next reaction.

[0197] To the material from the previous reaction, methanolic ammonia(0.5 M, 20 mL) was added and stirred for 16 h at room temperature. Thesolvent was removed under reduced pressure and the residue was purifiedby silica gel column chromatography (10% methanolethyl acetate) to givecompound 10 as a white solid: ¹H NMR (CD₃0D) 1.95-2.05 (m, 1H),2.30-2.40 (m, 1H), 3.70-3.80 (m, 2H), 3.80-3.90 (m, 2H), 3.95-4.05 (m,2H), 4.15-4.17(m, 1H), 4.28-4.30 (m, 1H), 4.65 (t, 1H), 4.70-4.80 (m,1H), 5.90 (d, 1H), 8.25 (s, 1H).

[0198](4-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)methan-1-ol(11)

[0199] To a solution of compound 1 (0.36, 1 mmol)) and2,2-dimethoxypropane (0.2 g, 2 mmol) in dimethylformamide (5 mL) wasadded p-toluenesulfonic acid (10 mg) at 70° C. After 48 h at 70° C., thereaction was concentrated in vacuo to afford a solid. The solid wasdissolved in methanol (1 mL), then triturated with ethyl ether (50 mL).The resultant crystals were collected by vacuum filtration to afford theintermediate 11.

[0200][(4-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(1R,2R,4R,5R)7,7dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)methoxy]-N-methylcarboxamide(12)

[0201] To a solution of compound 11 (90 mg, 0.25 mmol) in THF (1 mL) wasadded carbonyldiimidazole (162 mg, 1 mmol) at rt. After stirring for 2 h, excess reagent was quenched by adding a drop of water. Methylamine(40% aq. Solution, 0.5 mL) was added and stirring was continued foranother 16 h. The reaction mixture was concentrated in vacuo to afford agum. It was purified by prep.TLC [(silica gel, 10%MeOH-dichloromethane)] to afford compound 12.

[0202][(5-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(3S,2R,4R,5R)3,4dihydroxyoxolan-2-yl)methoxy]-N-methylcarboxamide(13) Compound 12 (50 mg) was taken in a mixture of acetic acid (8 mL)and water (2 mL) and heated at 90° C. for 16 h. Solvents were removedunder reduced pressure and the residue was purified by preparative TLC[methanol-dichloromethane (1:9)] to afford compound 13. ¹H NMR (CD₃OD)1.95-2.05 (m, 1H), 2.30-2.40 (m, 1H), 2.70 (s, 3H), 3.70-3.80 (m, 1H),3.80-3.90 (m, 1H), 3.954.05 (m, 2H), 4.20-4.40 (m, 4H), 4.65 (t, 1H),4.70-4.80 (m, 1H), 5.95 (d, 1H), 6.90 (bs, exchangeable, 1H), 8.20 (s,1H).

[0203][(5-16-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide(69)

[0204] This compound was prepared in a manner similar to that of 13substituting cyclopentyl amine for methyl amine: ¹H NMR (CD₃OD) 1.4-1.5(m, 2H), 1.5-1.6 (m, 2H), 1.6-1.7(m, 2H), 1.8-1.9 (m, 2H), 1.95-2.05 (m,1H), 2.30-2.40 (m, 1H), 3.70-3.80 (m, 1H), 3.80-3.90 (m, 2H), 3.95-4.05(m, 2H), 4.20-4.40 (m, 4H), 4.65 (t, 1H), 4.65-4.80 (m, 1H), 5.95 (d,1H), 8.15 (s, 1H)

EXAMPLE 7

[0205]

[0206]N-1(5-{6-1((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl]methoxycarboxamide(18)

[0207] Compound 14 (1.4 g, 3.07 mmol) was dissolved in dry DMF andsodium azide (3.00 g, 4.6 mmol) was added and heated at 65° C. for 16 h.The solvent was evaporated and the residue was subjected to aqueous workup and purified by flash column (100% ethyl acetate) to get 15.

[0208] A solution of 15 (314mg) in ethanol containing 10%Pd—C (10 mg) inan atmosphere to of hydrogen was stirred at room temperature for 16 h.Filtration followed by the evaporation of solvent gave compound 16.

[0209] CDI (100 mg) was added to 3 mL of dry methanol and stirred atroom temeprature for 15 min. The solvent was evaporated and the residuewas dissolved in dry THF (5 mL). Compound 16 (25 mg) was added to thesolution and the mixture was stirred at room temperature for 16 h. Thesolvent on evaporation followed by preparative TLC (5% MeOH: 95% DCM)purification gave the compound 17. Deprotection of 17 with 80% aqueousacetic acid followed by evaporation and purification by preparative TLC(5% MeOH: 95% DCM) gave compound 18 [MS 395.2 (M+1)].

[0210]N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S92R,4R5R)-3,4-dihydroxyoxolan-2-yl)methylcyclopentyloxycarboxamide(70)

[0211] Compound 70 was prepared as described above in Example 7substituting cyclopentanol for methanol [MS 489.3 (M+1)].

EXAMPLE 8

[0212]

[0213]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[methoxythioxomethyl)amino]methyl}oxolane-3,4-diol(71)

[0214] Compound 71 was prepared as described in Example 7 substitutingthioCDI for CDI [MS 411.2 (M+1)].

[0215]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yll(4S,2R,3R,5R)5-{[cyclopentyloxythioxomethyl)amino]methyl}oxolane3,4-diol(72)

[0216] Compound 72 was prepared as described in Example 7 substitutingthioCDI for CDI and cyclopentanol for methanol [MS 465.7 (M+1)].

[0217][(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)3,4-dihydroxyoxolan-2-yl)methythio]-N-cyclopentylcarboxamide(73).

[0218] Compound 73 was prepared in the manner of compound 22 bysubstituting cyclopentyl isocyanate for methyl isocyanate [MS 465.2(M+1)].

[0219]2-{6[((3R)oxolan-3-yl)ainio]purin-9yl}(4S,5S,2R,3R)5-{[(methylamniio)thioxomethylthio]methyl}oxolane3,4diol(74)

[0220] Compound 74 was prepared in the manner of compound 22 bysubstituting methyl isothiocyanate for methyl isocyanate [MS 427.2(M+1)].

[0221]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-{[(cyclopentylamino)thioxomethylthio]methyl}oxolane-3,4-diol(75)

[0222] Compound 75 was prepared in the manner of compound 22 bysubstituting cyclopentyl isothiocyanate for methyl isocyanate [MS 481.2(M+1)].

EXAMPLE 10

[0223]

[0224]N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](methylamino)carboxamide(24)

[0225] To a solution of 16 (30 mg) in acetonitrile a small amount (2 mg)of DMAP followed by methyl isocyanate (250 μL) was added and stirred atroom temperature for 16 h. The solvent was evaporated and the residuewas purified by preparative TLC (5% MeOH: 95% DCM) to obtain compound23. Deprotection of 22 with 80% aqueous acetic acid followed bypreparative TLC purification (5% MeOH: 95% DCM) gave compound 24 [MS394.2 (M+1)].

[0226]N-[(5-{6[((3R)oxolan-3yl)amino]purin-9-yl}(3S,2R,4R,5R)3,4-dihydroxyoxolan-2-yl)methyl](cyclopentylamino)carboxamide(76)

[0227] Compound 76 was prepared in the manner of compound 24substituting cyclopentyl isocyanate for methyl isocyanate and refluxingfor 16 h [MS 448.3 (M+1)].

[0228]2-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)5-({[(methylamino)thioxomethyl]amino}methyl)oxolane-3,4diol(77)

[0229] Compound 77 was prepared in the manner of compound 24substituting methyl isothiocyanate for methyl isocyanate and refluxingfor 16 h [MS 410.3 (M+1)].

[0230]2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(cyclopentylamnino)thioxomethyl]amino}methyl)oxolane3,4diol(78)

[0231] Compound 78 was prepared in the manner of compound 24substituting cyclopentyl isothiocyanate for methyl isocyanate andrefluxing for 16 h [MS 464.3 (M+1)].

[0232]N-[(5-{16[((3R)oxolan-3-yl)amino]purin-9-yI}(3S,2R,4R,5R3,4-dihydroxyoxolan-2-yl)methyl](ethylamino)carboxamide(79)

[0233] Compound 79 was prepared in the manner of compound 24substituting ethyl isocyanate for methyl isocyanate and refluxing for 16h [MS 408 (M+1)].

EXAMPLE 11

[0234]

[0235]3-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R3,4-dihydroxyoxolan-2-yl)methyl]-1,3-oxazolin-2-one(80)

[0236] Sodium hydride (40 mg, 60% in mineral oil) was added to asolution of oxazolidinone (85 mg, 1 mmol) in anhydrous DMF (2 mL). Tothis was added a solution of compound 15 (100 mg) in DMF (2 mL).Reaction mixture was allowed to stir at RT for 3 h. The solvent wasremoved under reduced pressure, the residue was dissolved in 80% aceticacid/water and heated at 80° C. for 16 h. Solvent was removed underreduced pressure and the residue was purified by preparative TLC (10%methanol-dichloromethane) to give compound 80 as a solid: (M+1)=405.38.

EXAMPLE 12

[0237] Binding Assays—DDT₁ Cells

[0238] Cell Culture

[0239] DDT cells (hamster vas deferens smooth muscle cell line) weregrown as monolayers in petri dishes using Dulbecco's Modified Eagle'sMedium (DMEM) containing 2.5 μg ml⁻¹ amphotericin B, 100 U ml⁻¹penicillin G, 0.1 mg ml⁻¹ streptomycin sulfate and 5% fetal bovine serumin a humidified atmosphere of 95% air and 5% CO₂. Cells were subculturedtwice weekly by dispersion in Hank's Balanced Salt Solution (HBSS)without the divalent cations and containing 1 mM EDTA. The cells werethen seeded in growth medium at a density of 1.2×10⁵ cells per plate andexperiments were performed 4 days later at approximately one daypreconfluence.

[0240] Membrane Preparations

[0241] Attached cells were washed twice with HBSS (2×10 ml), scrapedfree of the plate with the aid of a rubber policeman in 5 ml of 50 mMTris-HCI buffer pH 7.4 at 4° C. and the suspension homogenized for 10 s.The suspension was then centrifuged at 27,000×g for 10 min. The pelletwas resuspended in homogenization buffer by vortexing and centrifuged asdescribed above. The final pellet was resuspended in 1 vol of 50 mMTris-HCI buffer pH 7.4 containing 5 mM MgCl₂ for A₁ AdoR assays. For the[³⁵S]GTPγS binding assay the final pellet was resuspended in 50 mMTris-HCI pH 7.4 containing 5 mM MgCl_(2, 100) mM NaCl and 1 mMdithiothreitol. This membrane suspension was then placed in liquidnitrogen for 10 min, thawed and used for assays. The protein content wasdetermined by the method of Bradford (1976) using bovine serum albuminas standard.

[0242] Competitive Binding Assay Pig striatum were prepared byhomogenation in 50 mM Tris buffer (5× volume of tissue mass pH=7.4).After centrifilgation at 19,000 rpm for 25 minutes at 4° C., thesupernatant was discarded, and the process was repeated twice.Compositions of this invention were assayed to determine their affinityfor the A₁ receptor in a pig striatum membrane prep or a DDT, membraneprep. Briefly, 0.2 mg of pig striatal membranes or DDT, cell membraneswere treated with adenosine deaminase and 50 mM Tris buffer (pH=7.4)followed by mixing. To the pig membranes was added 2 μL of seriallydiluted DMSO stock solution of the compounds of this invention atconcentrations ranging from 100 microM to 10 nM. The control received 2microL of DMSO alone, then the antagonist [³H] 8-cyclopentylxanthine(CPX) for pig striatum or the agonist [³H]2-chloro-6-cyclopentyladenosine (CCPA) for DDT, membranes in Tris buffer(50 mnM, pH of 7.4) was added to achieve a final concentration of 2 nM.After incubation at 23 C for 2 h, the solutions were filtered using amembrane harvester using multiple washing of the membranes (3×). Thefilter disks were counted in scintillation cocktail affording the amountof displacement of triated CPX or by the competitive bindingcompositions of this invention. In the case of the DDT₁ cell membranes,some of the determinations of binding affinity (K_(i)) were made in thepresence of Gpp(NH)p as noted in Table 1 (note: Gpp(NH)p shifts thereceptor to a low affinity form). Greater than a 5 point curve was usedto generate K_(i)'s and the number of experiments is indicated in thecolumn marked in Table 1 below. TABLE 1 K_(i) - DDT₁ cell membraneK_(i)-DDT₁ In presence K_(i) - Pig Compound # cell membrane of Gpp (NH)pStriatum 41 668 nM — — 39 447 nM — — 39 447 nM — — 61 1571 nM — — 431700 nM — — 35 1012 nM — — 56 1236 nM — — 69 380 nM — — 42 3145 nM — —62 2191 nM — — 36 1517 nM — — 37 4236 nM — — 34 3464 nM — —  6 178 nM —228 nM 77 113 nM — — 78 357 nM — — 76 11590 nM — — 13 129 nM — — 73 183nM — — 75 62 nM — — 22 36 nM — — 67 2219 nM — — 22 36 nM — — 75 62 nM —— 69 380 nM — — 45 141 nM 46 — 135 nM — 49 — 145 nM — 47 — 109 nM — 48 —926 nM — 25 — 727 nM — 27 1611 nM 111 nM — 26 — 513 nM — 32 — 431 nM —54 — 229 nM — 60 — 239 nM — 53 245 nM 2109 nM — 51 — 87 nM — 55 252 nM962 nM — 52 — 1120 nM — 50 642 nM 1946 nM — 31 — 1091 nM — 44 — 1841 nM— 33 — 1713 nM — 30 2212 nM 1732 nM — 29 — 478 nM — 79 — 167 nM — 28 32nM 808 nM —

EXMIPLE 13

[0243] [³⁵S]GTγS Binding Assays

[0244] A₁-agonist stimulated [³⁵S]GTPγS binding was determined by amodification of the method described by Giersckik et al. (1991) andLorenzen et al. (1993). Membrane protein (30-50 μg) was incubated in avolume of 0.1 ml containing 50 mM Tris-HCI buffer pH 7.4, 5 mM MgCl₂,100 mM NaCl, 1 mM dithiothreitol, 0.2 units ml⁻¹ adenosine deaminase,0.5% BSA, 1 mM EDTA, 10 mM GDP, 0.3 nM [³⁵S]GTPγS and with or withoutvarying concentrations of CPA for 90 min at 30° C. Nonspecific bindingwas determined by the addition of 10 μM GTPγS. Agonist stimulatedbinding was determined as the difference between total binding in thepresence of CPA and basal binding determined in the absence of CPA.Previous reports have shown that agonist stimulated [³⁵S]GTPγS bindingwas dependent on the presence of GDP (Gierschik et al., 1991; Lorenzenet al., 1993; Traynor & Nahorski, 1995). In preliminary experiments, itwas found that 10 μM GDP gave the optimal stimulation of CPA dependent[³⁵S]GTPγS binding and this concentration was therefore used in allstudies. In saturation experiments, 0.5 nM [³⁵S]GTPγS was incubated with0.5-1000 nM GTPγS. At the end of the incubation, each suspension wasfiltered and the retained radioactivity determined as described above.TABLE 2 Compound # GTPγS CPA 100% 41 48% 39 67% 63 100% 64 99% 71 98% 7495% 72 93% 59 82% 65 81% 80 80% 72 93% 18 77% 70 76% 58 79% 57 67% 3967% 61 59% 43 53% 35 52% 56 52% 69 50% 42 47% 62 42% 36 41% 37 30% 3417% 38 1% 40 −6%  6 48% 77 101% 78 95% 13 77% 73 109% 75 91% 22 98% 6759% 68 76% 22 98% 75 91% 69 50% 45 77% 45 77% 46 77% 49 89% 47 84% 4870% 25 80% 27 44% 26 73% 32 91% 54 93% 60 77% 53 85% 55 82% 52 77% 5088% 30 41% 28 69%

EXAMPLE 14

[0245] cAMP Assay

[0246] A scintillation proximity assay (SPA) using rabbit antibodiesdirected at cAMP using an added tracer of adenosine 3′,5′-cyclicphosphoric acid 2′-O-succinyl-3-[¹²⁵I]iodotyrosine methyl ester andfluoromicrospheres containing anti-rabbit specific antibodies asdescribed by Amersham Pharmacia Biotech (Biotrak cellular communicationassays). Briefly, DDT₁ cells were cultured in clear bottomed 96 wellmicrotiter plates with opaque wells at concentrations between 10⁴ to 10⁶cells per well in 40 μl of HBSS at 37° C. (5% CO₂ and 95% humidity). Thepartial or full A₁ agonists (5 μl) of this invention were incubated atvarious concentrations with the DDT₁ cells in the presence of rolipram(50 μM), and 5 μM forskolin for 10 min at 37° C. The cells wereimmediately lysed by treatment 5 μl of 10% dodecyltrirnethylammoniumbromide followed by shaking using rnicroplate shaker. After incubationof the plate for 5 minutes, an imnuunoreagent solution (150 μlcontaining equal volumes of tracer, antiserum, and SPA fluorospheres)was added to each well followed by sealing the plate. After 15-20 h at23° C., the amount of bound [¹²⁵] cAM to the fluoromicrospheres wasdetermined by counting in a microtitre plate scintillation counter for 2minutes. Comparison of counts with standard curves generated for cAMPusing a similar protocol afforded the cAMP present after cell lysis.Results are presented normalized to the full agonistN-6-cyclopentyladenosine, CPA. Thus, the fall agonist CPA diminished theamount of forskolin induced cAMP generation back to basal levels. TABLE3 Compound # cAMP CPA 100% 41 17% 39 45% 63 115% 64 110% 71 94% 74 82%72 103% 58 78% 59 115% 65 95% 80 64% 72 103% 18 86 70 79% 57 73% 39 45%61 53% 43 28% 35 −4% 56 43% 69 18% 42 16% 62 23% 36 10% 37 −6% 34 −20%38 −25% 40 −14%  6 See Figure 69 18%

EXAMPLE 15

[0247] Methods

[0248] Guinea pigs of either sex weighing 250-300 g were anesthetizedwith methoxyflurane and killed by cervical dislocation. The hearts werequickly removed and rinsed in ice-cold Krebs-Henseleit solution. Theaorta was cannulated and the heart retrogradely perfused at a constantflow of 10 ml min⁻¹ with modified Krebs-Henseleit solution containing(mM): NaCL 117.9, KCl 4.8, CaCl₂ 2.5, MgSO₄ 1.18, KH₂PO₄ 1.2, Na₂EDTA0.5, ascorbic acid 0.14, glucose 5.5, pyruvic acid (sodium salt) 2.0,and NaHCO₃ 25. The K—H solution was oxygenated with 95% oxygen and 5%CO₂, pH 7.4, and temperature maintained at 36° C.

[0249] Hearts were electrically paced at a cycle length of 290-300 ms(unless otherwise indicated) using a bipolar electrode placed on theright atrium or ventricle. The stimulator, an interval generator (Model1830, WPI, Sarasota, Fla., U.S.A.) delivered stimuli through a stimulusisolation unit (Model 1880, WPI) as square wave pulses of 3 ms induration and at least twice the threshold intensity. The stimulus-to-Hisbundle (S—H) interval was used as index of AV nodal conduction time andwas measured on-line during constant atrial pacing from microcomputerwith a DT-208 1A interface board (Axon Instruments, Burlingame, Calif.,U.S.A.) In experiments to study the chronotropic effect (effect on heartrate) of A₁ AdoR agonists, the hearts were allowed to beatspontaneously. An atrial electrogram was used to record the electricalactivity of the atria and to measure the heart rate.

[0250] Coronary perfusion pressure was measured using a pressuretransducer that was connected to the aortic cannula via a T-connector.Coronary perfusion pressure (in mmHg) was monitored throughout anexperiment and recorded on a 4-channel Gould strip-chart recorder (GouldRS3400, Cleveland, Ohio, U.S.A.). Coronary conductance (in ml min⁻¹mmHg⁻¹) was calculated as the ratio of coronary perfusion rate (10 mlmin⁻¹) and perfusion pressure (mmHg).

[0251] Monophasic action potentials (MAP) were recorded using a pressurecontact silver-silver chloride electrode (Langendorf Probe, EPTechnologies, Inc., Sunnyvale, Calif., U.S.A.) placed on the surface ofthe left atrium. The signals were amplified and filtered by an isolatedbiological amplifier (IsoDam, WPI) and displayed in real time on adigital oscilloscope (2201 Tektronix, Inc., Beaverton, Oreg., U.S.A.).Signals were considered adequate if they were stable for at least 5 minand the amplitudes of the MAPs exceeded 10 mV. The data were digitizedat 2 kHz by a DT-2801A digitizing board (Data Translation, Marlboro,Mass., U.S.A.) and stored using the Snapshot data acquisition program(Snapshot Storage Scope, HEM Data Corp., Southfield, Mich., U.S.A.) forlater analysis. The duration of the atrial monophasic action potentialwas measured at 90% repolarization (MAPD₉₀), using the Snapshot program.After completion of dissection and instrumentation, the hearts wereallowed to equilibrate for 30 min before the experiments were begun.Whenever the baseline and post-intervention (washout) values differed bymore than 15% the data were discarded. Approximately 60-70% of theexperiments conformed with this criteria.

[0252] Partial A₁ (Results and Discussion)

[0253] The effects of compound 6 are illustrated in FIGS. 1-3. Asillustrated in FIG. 1 (panel C) in guinea pig isolated perfused hearts,compound 6 causes a concentration-dependent and significant increase inAV nodal conduction time (measured as stimulus-to-His bundle interval)without causing second-degree AV block at any concentration tested. Thatis, compound 6 has a negative dromotropic effect (FIG. 1, panel C), andits potency (EC₅₀ value=concentration that causes half-maximal effect)to prolong S—H interval is 2.8±1.3 μM. The selective A₁ adenosinereceptor antagonist CPX (50 nM) antagonizes the prolongation of S—Hinterval caused by compound 6 indicating that the effect of compound 6is mediated by the A₁ adenosine receptor subtype (FIG. 2). On the otherhand, compound 6 had no effect on other cardiac A₁ AdoR mediated actionsof adenosine and full A₁ AdoR agonists (FIG. 1). Specifically, compound6 did not slow heart rate (i.e, has no negative drqmotropic effect; FIG.1, panel A) or shorten the atrial monophasic action potential (FIG. 1,panel B). In contrast to compound 6 (as shown in FIG. 1), the fill A,AdoR agonists CPA and CCPA slowed heart rate (panel A), shortened themonophasic atrial action potential (panel B), prolonged the S—H intervaland caused second-degree AV block (panel C). Compound 6 had a weakpotency (EC₅₀=31±5.1 μM) to cause coronary vasodilation, an A₂AAdoR-mediated effect. Hence Compound 6 is at least 10-fold more potent(selective) to cause S—H interval prolongation than to increase coronaryconductance. Another important pharmacological property of a truepartial agonist(s) is to attenuate the effect(s) of a full agonits). Inthis regard, as shown in FIG. 3, compound 6 indeed antagonizes thenegative dromotropic effect (S—H interval prolongation) of the full A₁AdoR agonist CPA, a finding that strongly supports the conclusion thatcompound 6 is a true partial A₁ AdoR agonist.

[0254] In summary, compound 6 is a partial agonist of the A₁ AdoR thatcauses moderate negative dromotropic effect without causing second- orthird-degree AV block, bradycardia or shortening of atrial monophasicaction potential.

What we claim is:
 1. A composition of matter having the formula:

wherein X¹═O, S, NR⁶; Y═O, S, N—CN, N—OR⁷; Z═O, S, NR⁸; R¹ is amonocyclic or polycyclic heterocyclic group containing from 3 to 15carbon atoms wherein at least one carbon atom is substituted with anatom or molecule selected from the group consisting of N, O, P andS—(O)₀₋₂ and wherein R¹ does not contain an epoxide group; R² isselected from the group consisting of hydrogen, halo, CF₃, and cyano; R³and R⁴ are each independently selected from the group consisting ofhydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are independentlyselected from the group consisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl,alkynyl, aryl, heterocyclyl, and heteroaryl are optionally substitutedwith 1 to 3 substituents independently selected from the group of halo,NO₂, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²²,SO₂NR²⁰CON(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂,NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²²,SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂and each optional heteroaryl, aryl, and heterocyclyl substituent isfurther optionally substituted with halo, NO₂, aLkyl, CF₃, amino, mono-or di- alkylamino, alkyl or aryl or heteroaryl amide, NR²²COR²²,NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰,OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R⁵ isselected from the group consisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl,alkynyl, aryl, heterocyclyl and heteroaryl are optionally substitutedwith from 1 to 3 substituents independently selected from the groupconsisting of halo, alkyl, NO₂, heterocyclyl, aryl, heteroaryl, CF₃, CN,OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂,SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²²,NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²²,NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰,and OCON(R²⁰)₂ and each optional alkyl, heteroaryl, aryl, andheterocyclyl substituent is further optionally substituted with halo,NO₂, alkyl, CF₃, amino, mono- or di- alkylamino, alkyl or aryl orheteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂,NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R20)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂, SR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R⁶ is selected from the groupconsisting of H, C₁₋₆ alkyl and aryl optionally substituted with halo,CN, CF₃, OR²⁰ and N(R²⁰)₂,; R⁷ and R⁸ are independently selected fromthe group consisting of H, and C₁-C₁₅ alkyl optionally substituted withone aryl substituent that is optionally substituted with halo or CF₃;R²⁰ is selected from the group consisting of H, C₁₋₁₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, wherein thealkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituentsare optionally substituted with from 1 to 3 substituents independentlyselected from halo, alkyl, mono- or dialkylamino, alkyl or aryl orheteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl; and R²²is selected from the group consisting of hydrogen, C₁₋₁₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, wherein thealkyl, alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl substituentsare optionally substituted with from 1 to 3 substituents independentlyselected from halo, alkyl, mono- or dialkylamino, alkyl or aryl orheteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl whereinwhen Z═NR⁸ then R⁵ and R⁸ may bond to form a 4 or 5 or 6 memberedsaturated or unsaturated ring; wherein when X¹═NR⁶ and when Z═NR⁸, thenR⁶ and R⁸ may bond to form a 4 or 5 or 6 membered saturated orunsaturated ring; and wherein when X¹═N⁶ and Y═O or S, then R⁵ and R⁶may bond to form a 5 or a 6 membered saturated or unsaturated ring. 2.The composition of claim 1 wherein Y═O, S; R² is selected from hydrogen,and halo; R³ and R⁴ are independently selected from the group consistingof hydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′, and R″ areindependently selected from the group consisting of C₁₋₁₅ alkyl,heterocyclyl, aryl, and heteroaryl, which alkyl, aryl, heterocyclyl, andheteroaryl are optionally substituted with from 1 to 2 substituentsindependently selected from the group of halo, NO₂, heterocyclyl, aryl,heteroaryl, CF₃, CN, OR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰,CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²² and each optional heteroaryl, aryl,and heterocyclyl substituent is optionally substituted with halo, NO₂,alkyl, CF₃, amino, mono- or di- alkylamino, CN, or OR²⁰; R⁵ is selectedfrom the group consisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl, aryl,heterocyclyl and heteroaryl are optionally substituted with from 1 to 3substituents independently selected from the group of halo, alkyl,heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, P(O)(R)₂, NR²⁰COR²², NR²⁰CO₂R²²,NR²⁰CON(R²⁰)₂, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, and each optional alkyl,heteroaryl, and aryl substituent is optionally substituted with halo,alkyl CF₃, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂,SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R²⁰ is a member selectedfrom the group consisting of H, C1-15 alkyl, aryl, and heteroaryl, whichalkyl, aryl, and heteroaryl are optionally substituted with 1 to 2substituents independently selected from halo, alkyl, aryl, mono- ordialkylamino, CN, O—C₁₋₆ alkyl, CF₃; and R²² is a member selected fromthe group consisting of hydrogen, C₁₋₁₅ alkyl, aryl, and heteroaryl,which alkyl, aryl, and heteroaryl are optionally substituted with 1 to 2substituents independently selected from halo, aLkyl, mono- ordialkylarino, aLkyl or CN, O—C₁₋₆ alkyl, and CF₃ wherein when Z═NR⁸ thenR⁵ and R⁸ may bond to form a 4 or 5 or 6 membered saturated orunsaturated ring; wherein when X¹═NR⁶ and when Z═NR⁸, then R⁶ and R⁸ maybond to form a 4 or 5 or 6 membered saturated or unsaturated ring; andwherein when X¹═NR⁶ and Y═O or S, then R⁵ and R⁶ may bond to form a 5 ora 6 membered saturated or unsaturated ring.
 3. The composition of claim1 wherein Y═O, S; R² is selected from the group consisting of hydrogen,and halo; R³ and R⁴ are independently selected from the group consistingof hydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′, and R″ are eachindependently selected from the group consisting of C₁₋₁₀ alkyl, aryl,and heteroaryl, which alkyl, aryl, and heteroaryl are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group of halo, NO₂, aryl, heteroaryl, CF₃, CN, OR²⁰, N(R²⁰)₂,S(O)R²², SO₂R²², NR²⁰COR²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰SO₂R²², andeach optional heteroaryl, aryl, and heterocyclyl substituent isoptionally substituted with halo, NO₂, alkyl, CF₃; R⁵ is selected fromthe group consisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, heterocyclyl, aryl,and heteroaryl, which alkyl, alkenyl, aryl, heterocyclyl and heteroarylare optionally substituted with 1 to 3 substituents independentlyselected from the group of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰,SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, P(O)(OR²⁰)₂,NR²⁰COR²², NR²²CO₂R²², NR²⁰CON(R²⁰)₂, COR²⁰CO₂R²⁰, CON(R²⁰)₂, and eachoptional alkyl, heteroaryl, and aryl substituent is optionallysubstituted with halo, alky, CF₃, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂,S(O)₃R20, P(O)(OR²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R⁶ isselected from the group consisting of H, C₁₋₆ allyl optionallysubstituted with CF₃, and OR²⁰; R⁸ is independently selected from thegroup consisting of H, and C₁-C₈ alkyl optionally substituted with onearyl substituent that is optionally substituted with halo or CF₃; R²⁰ isa member selected from the group consisting of H, C₁₋₆ alkyl, and aryl,which alkyl, and aryl, are optionally substituted with 1 substituentindependently selected from halo, alkyl, aryl, mono- or dialkylamino,CN, O—C₁₋₆ alkyl, CF₃; and R²² is a member selected from the groupconsisting of hydrogen, C₁₋₆ alkyl and aryl, which alkyl and aryl areoptionally substituted with 1 substituent independently selected fromhalo, alkyl, mono- or dialkylamino, alkyl or CN, O—C₁₋₆ alkyl, and CF₃wherein when Z═NR⁸ then R⁵ and R⁸ may bond to form a 4 or 5 or 6membered saturated or unsaturated ring; wherein when X¹═NR⁶ and whenZ═NR⁸, then R⁶ and R⁸ may bond to form a 4 or 5 or 6 membered saturatedor unsaturated ring; and wherein when X¹═NR⁶ and Y═O or S, then R⁵ andR⁶ may bond to form a 5 or a 6 membered saturated or unsaturated ring.4. The composition of claim 1 wherein Y═O, S; R² is selected from thegroup consisting of hydrogen, and halo; R³ and R⁴ are each independentlyselected from the group consisting of hydrogen, and —(CO)—R′and —(CO)—R″wherein R′, and R″ are independently selected from the group consistingof C₁₋₆ alkyl, and aryl, which alkyl and aryl are optionally substitutedwith from 1 to 2 substituents independently selected from the group ofhalo, NO₂, aryl, CF₃, CN, OR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², NR²⁰COR²², andeach optional aryl substituent is optionally substituted with halo, NO₂,alkyl, CF₃; R⁵ is selected from the group consisting of C₁₋₁₅ alkyl,C₂₋₁₅ alkenyl, aryl, and heteroaryl, which alkyl, alkenyl, aryl, andheteroaryl are optionally substituted with from 1 to 3 substituentsindependently selected from the group of halo, alkyl, aryl, heteroaryl,CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰,NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and whereineach optional alkyl, heteroaryl, and aryl substituent is optionallysubstituted with halo, alkyl, CF₃, CO₂R²⁰, CON(R²⁰)₂, S(O)₃R²⁰, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R⁶ is selected from the groupconsisting of H, C₁₋₄ alkyl; R⁸ is independently selected from the groupconsisting of H, and C₁-C₈ alkyl; R²⁰ is a member selected from thegroup consisting of H, C₁₋₆ alkyl, and aryl, which alkyl and aryl areoptionally substituted with 1 substituent independently selected fromhalo, alkyl, aryl, mono- or dialkylamino, CN, O—C₁₋₆ alkyl, CF₃; and R²²is a member selected from the group consisting of hydrogen, C₁₋₆alkyland aryl, which alkyl and aryl are optionally substituted with 1substituent independently selected from halo, alkyl or CN, O—C₁₋₆alkyl,and CF₃ wherein when Z═NR⁸ then R⁵ and R⁸ may bond to form a 4 or 5 or 6membered saturated or unsaturated ring; wherein when X¹═NR⁶ and whenZ═NR⁸, then R⁶ and R⁸ may bond to form a 4 or 5 or 6 membered saturatedor unsaturated ring; and wherein when X¹═NR⁶ and Y═O or S, then Rs andR⁶ may bond to form a 5 or a 6 membered saturated or unsaturated ring.5. The composition of claim 1 wherein Y═O, S; R² is selected from thegroup consisting of hydrogen, and halo; R³ and R⁴ are each independentlyselected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″wherein R′, and R″ are each independently selected from the groupconsisting of C₁₋₆ alkyl which alkyl is optionally substituted with 1substituent selected from the group consisting of aryl, CF₃, CN, OR²⁰,N(R²⁰)₂, and wherein each optional aryl substituent is optionallysubstituted with halo, NO₂, alkyl, CF₃; R⁵ is selected from the groupconsisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and aryl, which alkyl, alkenyl,and aryl, is optionally substituted with from 1 to 2 substituentsindependently selected from the group of halo, alkyl, aryl, heteroaryl,CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)R²⁰, NR²⁰COR²²,NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and wherein each optional alkyl andaryl substituent is optionally substituted with halo, alkyl, CF₃,CO₂R²⁰, S(O)₃R²⁰, CN, or OR²⁰; R⁶ is selected from the group consistingof H, C₁₋₃ alkyl; R⁸ is independently selected from the group consistingof H, and C₁-C₃ alkyl; R₂₀ is selected from the group consisting of H,C₁₋₆ alkyl, which alkyl is optionally substituted with aryl; and R₂₂ isa member selected from the group consisting of hydrogen and C₁₋₆ whereinwhen Z═NR⁸ then R⁵ and R⁸ may bond to form a 4 or 5 or 6 memberedsaturated or Air unsaturated ring; wherein when X¹═NR⁶ and when Z═NR⁸,then R⁶ and R⁸ may bond to form a 4 or 5 or 6 membered saturated orunsaturated ring; and wherein when X¹═NR⁶ and Y═O or S, then R⁵ and R⁶may bond to form a 5 or a 6 membered saturated or unsaturated ring. 6.The composition of claims 1 or 2 or 3 or 4 wherein X¹═O; Y═O, S; Z═NR⁸;and R² is selected from the group consisting of hydrogen, and halo. 7.The composition of claims 1 or 2 or 3 or 4 wherein X¹═NR⁶; Y═O, S; Z═O;and R² is selected from the group consisting of hydrogen, and halo. 8.The composition of claims 1 or 2 or 3 or 4 wherein X¹═S; Y═O or S;Z═NR⁸; and R² is selected from the group consisting of hydrogen, andhalo.
 9. The composition of claims 1 or 2 or 3 or 4 wherein X¹═NR⁶; Y═Oor S; Z═NR⁸; and R² is selected from the group consisting of hydrogen,and halo.
 10. The composition of claim 5 wherein X¹═O; Y═O or S; andZ═N⁸.
 11. The composition of claim 10 wherein R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, —(CO)—R′and —(CO)—R″ wherein R′, and R″ are each independently selected from thegroup consisting of C₁₋₆ alkyl; R⁵ is selected from the group consistingof C₁₋₈ alkyl, C₂₋₈ alkenyl, and aryl, which alkyl, alkenyl, and aryl,are each optionally substituted with from 1 to 2 substituentsindependently selected from the group of halo, alkyl, aryl, heteroaryl,CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰, NR²⁰COR²²,NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and each optional alkyl, and arylsubstituent is optionally substituted with halo, alkyl, CF₃, CO₂R²⁰,S(O)₃R²⁰, CN, or OR²⁰; and R⁸ is independently selected from the groupconsisting of H., and C₁-C₃ alkyl and wherein R⁵ and R⁸ may bond to forma 4 or 5 or 6 membered saturated ring.
 12. The composition of claim 11wherein R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′, and R″ areeach independently selected from the group consisting of methyl,isopropyl, or cyclopentyl; R⁵ is selected from the group consisting ofC₁₋₈ alkyl, and C₂₋₈ alkenyl, which alkyl and alkenyl are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group of halo, aLkyl, ayl, CF₃, CN, OR²⁰, S(O)₃R²⁰, CO₂R²⁰, andwherein each optional alkyl, and aryl substituent is optionallysubstituted with halo, alkyl, CF₃, CO₂R²⁰, S(O)₃R²⁰, CN, or OR²⁰; and R⁸is selected from the group consisting of H, and C₁-C₃ alkyl and whereinR⁵ and R⁸ may bond to form a 4 or 5 or 6 membered saturated ring. 13.The composition of claim 11 wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen, —(CO)—R′, and —(CO)—R″wherein R′, and R″ are each methyl; R⁵ is selected from the groupconsisting of C₁₋₈ alkyl, and C₂₋₈ alkenyl, which alkyl, and alkenyl areoptionally substituted with from 1 to 2 substituents independentlyselected from the group of alkyl, aryl, OR²⁰, CO₂R²⁰, and wherein eachoptional alkyl and aryl substituent are optionally substituted withhalo, alkyl, CF₃, CO₂R²⁰, or OR²⁰; R⁸ is selected from the groupconsisting of H, and C₁-C₃ alkyl; and R₂₀ is a selected from the groupconsisting of H, C₁₋₆ alkyl, which alkyl is optionally substituted witharyl, wherein RW and R⁸ may bond to form a 4 or 5 or 6 memberedsaturated ring.
 14. The composition of claim 11 wherein R³ and R⁴ areeach hydrogen; R⁵ is selected from the group consisting of C₁₋₈ alkyl,and C₂₋₈ alkenyl, which alkyl and alkenyl are optionally substitutedwith from 1 to 2 substituents independently selected from the group ofalkyl, aryl, OR²⁰, CO₂R²⁰, and wherein each optional alkyl and arylsubstituent is optionally substituted with halo, or CO₂R²⁰; R⁸ isselected from the group consisting of H, and C₁-C₃ alkyl; and R₂₀ is amember selected from the group consisting of H, and C₁₋₃ alkyl, whichalkyl is optionally substituted with aryl wherein R⁵ and R⁸ may bond toform a 4 or 5 or 6 membered saturated ring.
 15. The composition of claim11 wherein R³ and R⁴ are each hydrogen; R⁵ is selected from the groupconsisting of C₁₋₈ alkyl, and C₂₋₈ alkenyl, which alkyl, and alkenyl,are optionally substituted with from 1 to 2 substituents independentlyselected from the group of aryl, OR²⁰, C₂R²⁰, and wherein each optionalaryl substituent is optionally substituted with halo; R⁸ isindependently selected from the group consisting of H, and C₁-C₃ alkyl;and R₂₀ is selected from the group consisting of H, and methyl whereinR⁵ and R⁸ may bond to form a 4 or 5 or 6 membered saturated ring. 16.The composition of claims 6 or 10 or 11 or 12 or 13 or 14 wherein R²═H.17. The composition of claim 15 wherein R²═H.
 18. The composition ofclaim 17 wherein Y═O; R⁸ is H; and R⁵ is selected from the groupconsisting of methyl, ethyl, n-propyl, n-butyl, cyclopentyl, benzyl, (4fluorophenylmethyl), isopropyl, cyclopropyl, cyclohexyl, allyl,2-carboethoxyethyl, carbomethoxymethyl, 2-phenylcyclopropyl, cyclobutyl,2-benzyloxycyclopentyl, 2-hydroxycyclopentyl, 2-carbomethoxycyclopentyl,2-(3-carboethoxy-norborn-5-enyl), 2-(3-carboxy-norborn-5-enyl),2-(3-carboethoxy-norbornyl), and 2-carboxycyclopentyl.
 19. Thecomposition of claim 17 wherein Y═S; R⁵ is methyl, and R⁸ is methyl. 20.The composition of claim 17 wherein Z═NR⁸ and R⁵ and R⁸ bond to form a 5or 6 membered saturated rings.
 21. The composition of claim 17 whereinY═S; R⁸ is H; and R⁵ is selected from the group consisting of methyl,ethyl, n-propyl, n-butyl, cyclopentyl, benzyl, isopropyl, cyclopropyl,cyclohexyl, allyl, cyclobutyl, 2-benzyloxycyclopentyl,2-hydroxycyclopentyl.
 22. The composition of claim 5 wherein X¹═NR⁶; Y═Oor S; Z═O; and R² is H.
 23. The composition of claim 22 wherein R³ andR⁴ are independently selected from the group consisting of hydrogen,—(CO)—R′, and —(CO)—R″ wherein R′, and R″ are each methyl; R⁵ isselected from the group consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, andaryl, which alkyl, alkenyl, and aryl, are optionally substituted withfrom 1 to 2 substituents independently selected from the group of halo,alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,S(O)₃R²⁰, NR²⁰COR²², NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and wherein eachoptional allyl, and aryl substituent is optionally substituted withhalo, alkyl, CF₃, CO₂R²⁰, S(O)₃R²⁰, CN, or OR²⁰; and R⁶ is selected fromthe group consisting of H, and C₁-C₃ alkyl wherein when X¹═NR⁶ then R⁵and R⁶ may bond to form a 4 or 5 or 6 membered saturated or unsaturatedring.
 24. The composition of claim 22 wherein R³ and R⁴ are hydrogen; R⁵is C₁₋₈ alkyl, which alkyl is optionally substituted with 1 substituentindependently selected from the group consisting of aryl, OR²⁰,CO₂R²⁰,CON(R²⁰)₂, and wherein each optional aryl substituent is optionallysubstituted with halo, alkyl, CF₃, CO₂R²⁰; and R⁶ is independentlyselected from the group consisting of H, and C₁-C₃ alkyl wherein whenX¹═NR⁶ then R⁵ and R⁶ may bond to form a 4 or 5 or 6 membered saturatedor unsaturated ring.
 25. The composition of claim 22 wherein R³ and R⁴are each hydrogen; R⁵ is a C₁₋₈ alkyl; and R⁶ is selected from the groupconsisting of H, and C₁-C₃ alkyl wherein when=NR⁶ then R⁵ and R⁶ mayform a 4 or 5 or 6 membered saturated or unsaturated ring.
 26. Thecomposition of claim 25 wherein R⁵ is methyl or cyclopentyl and R⁶═H.26. The composition of claim 25 wherein X¹═NR⁶, Y═O, and R⁵ and R⁶ bondto form a S membered unsaturated ring wherein R⁵ and R⁶ together formCH═CH.
 28. The composition of claim 5 wherein X¹═S; Y═O or S; Z═NR⁸; andR² is H.
 29. The composition of claim 28 wherein R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, —(CO)—R′and —(CO)—R″, wherein R′ and R″ are each methyl; R⁵ is selected from thegroup consisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and aryl, which alkyl,alkenyl and aryl, are optionally substituted with from 1 to 2substituents independently selected from the group consisting of halo,alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,S(O)₃R²⁰, NR²⁰COR²², NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and wherein eachoptional alkyl and aryl substituent is further optionally substitutedwith halo, alkyl, CF₃, CO₂R²⁰, S(O)₃R²⁰, CN, or OR²⁰; and R⁸ is selectedfrom the group consisting of H, and C₁-C₃ alkyl.
 30. The composition ofclaim 28 wherein R³ and R⁴ are each hydrogen; R⁵ is C₁₋₈ alkyl that isoptionally substituted with 1 substituent selected from the groupconsisting of aryl, OR²⁰, CO₂R²⁰, CON(R²⁰)₂, and wherein each optionalaryl substituent is optionally substituted with halo, alkyl, CF₃,CO₂R²⁰; and R⁸ is H.
 31. The composition of claim 28 wherein R³ and R⁴are each hydrogen; R⁵ is C₁₋₈ alkyl; and R⁸ is H.
 32. The composition ofclaim 31 wherein R⁵ is methyl or cyclopentyl.
 33. The composition ofclaim 5 wherein X¹═NR⁶; Y═O or S; Z═NR⁸; and R² is H.
 34. Thecomposition of claim 33 wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″wherein R′, and R″ are each methyl; R⁵ is selected from the groupconsisting of C₁₋₈ alkyl, C₂₋₈ alkenyl, and aryl, which alkyl, alkenyl,and aryl, are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, alkyl, aryl,heteroaryl, CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, S(O)₃R²⁰,NR²⁰COR²², NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R₂₀)₂, and wherein each optionalalkyl, and aryl substituent is optionally substituted with halo, alkyl,CF₃, CO₂R²⁰, S(O)₃R²⁰, CN, or OR²⁰; R⁶ is selected from the groupconsisting of H, and C₁-C₃ alkyl; and R⁸ is selected from the groupconsisting of H, and C₁-C₃ alkyl, wherein R⁶ and R⁸ may bond to form a 4or 5 or 6 membered saturated or unsaturated ring.
 35. The composition ofclaim 33 wherein R³ and R⁴ are hydrogen; R⁵ is selected from the groupconsisting of C₁₋₈ alkyl, which alkyl is optionally substituted with 1substituent independently selected from the group consisting of aryl,OR²⁰, CO₂R²⁰, CON(R²⁰)₂, and each optional aryl substituent is furtheroptionally substituted with halo, alkyl, CF₃, CO₂R²⁰; and R⁸is H. 36.The composition of claim 33 wherein R³ and R⁴ are each hydrogen; R⁵ isC₁₋₈ alkyl; R⁶═H; and R⁸ is H.
 37. The composition of claim 36 whereinR⁵ is methyl or cyclopentyl.
 38. The composition of claim 1 wherein R¹is mono or polysubstituted with one or more compounds selected from thegroup consisting of halogen, oxo, hydroxyl, lower alkyl, substitutedlower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl,heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, nitro, cyano and mixtures thereof.
 39. The composition ofclaim 1 wherein R¹ is a monocyclic, bicyclic, or tricyclic cycloalkylgroup containing from 3 to 15 carbon atoms wherein at least one carbonatom is substituted with an atom or molecule selected from the groupconsisting of O or S—(O)₀₋₂.
 40. The composition of claim 39 wherein R¹is mono or polysubstituted with one or more compounds selected from thegroup consisting of halogen, oxo, hydroxyl, lower alkyl, substitutedlower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl,heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, nitro, cyano and mixtures thereof.
 41. The composition ofclaim 1 wherein R₁ is:

wherein R₁′, R₁″, R₁′″, and R₁″″ are each individually selected from thegroup halogen, hydroxyl, lower alkyl, substituted lower allyl, alkoxy,aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,nitro, and cyano, and X is O, or S(—O)₀₋₂.
 42. The composition of claim41 wherein R₁′″ and R₁″″ is a single oxygen atom.
 43. The composition ofclaim 42 wherein R₁′, R₁″, R₁′″, and R₁″″ are each individually selectedfrom the group H, lower alkyl, substituted lower alkyl, alkoxy, aryl,and substituted aryl.
 44. The composition of claim 42 wherein R₁′, R₁″,R₁′″, and R₁″″ are each individually selected from the group hydrogen,lower alkyl, and substituted lower alkyl.
 45. The composition of claim 1wherein R¹ is selected from the group consisting of:

wherein each R is individually selected from the group consisting of H,lower alkyl, and substituted lower alkyl and wherein X is O, orS(—O)₀₋₂.
 46. The composition of claims 1 or 2 or 3 or 4 or 5 or 6 or 7or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or32 or 33 or 34 or 35 or 36 or 37 wherein R₁ is selected from the groupconsisting of 3-tetrahydrofuranyl, 3-tetrahydrothiofiuranyl, 4-pyranyl,and 4 thiopyranyl.
 47. The composition of claims 1 or 2 or 3 or 4 or 5or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 wherein R₁is3-tetrahydrofuranyl.
 48. The composition of claim 1 wherein the compoundis selected from(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-methylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-ethylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-propylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-butylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-benzylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(4-fluorophenyl)methyl]carboxamide;{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclohexylcarboxamide;{(5-{6-[((3R)oxolan-3-yl)anmino]purin-9-yl}(3S,2R,4R,5R)-3,4-2“z 0dihydroxyoxolan-2-yl)methoxy]-N-(methylethyl)carboxamide;{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2-yl)methoxy]-N-cyclopropylcarboxamide;Methyl2-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylate;Ethyl3-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicylo[2.2.1]hept-5-ene-2-carboxylate;Ethyl3-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicylo[2.2.1]heptane-2-carboxylate;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4dihydroxyoxolan-2-yl)methoxy]-N-[(lR,2R)-2-(phenylmethoxy)cyclopentyl]carboxamide;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-[(1S,2S)-2-(phenylmethoxy)cyclopentyl]carboxamide;(5-{6-[((3R)oxolan-3-yl)amino}purin-9-yl }(3 S ,2R,4R,5R)-3,⁴-dihydroxyoxolan-2-yl)methoxy]-N-cyclobutylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino}purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-(2-phenylcyclopropyl)carboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S, 2R, 4R,5R)-³,⁴-dihydroxyoxolan-2-yl)methoxy]-N-prop-2-enylcarboxamide; Ethyl3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolane-2-yl)methoxy}carbonylamino}propanoate;Methyl 2-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolane-2-yl)methoxy}carbonylamino}acetate;{(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N,N-dimethylcarboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(methylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(ethylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,SR)-5-({[(methylethyl)amiiio]thioxomethoxy}methyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(butylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amiino]purin-9-yl}(4S,2R,3R,5R)-5-{[(propylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(⁴S,²R,³R,5R)-5-[(piperidylthioxomethoxy)methyl]oxolane-3,4-diol;2-:2io{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(cyclopentylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(⁴S,²R,³R,SR)-5-[(pyrrolidinylthioxomethoxy)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(dimethylamino)thioxomethoxy]methyl}oxolane-3,4&iol;2-{6-[((3R)oxolan-3-yl)amino]puin-9-yl}(4S,2R,3R,5R)-5-({[benzylamino]thioxomethoxy}methyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R5-({[cyclohexylamino]thioxomethoxy}methyl)oxolane-3,4diol;2-{6-[((3R)oxolan-3-yl)amfio]purin-9-yl}(4S,2R,3R,5R)-5-[({[(1S,2S)-2-(phenylmethoxy)cyclopentyl]amino}thioxomethoxy)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-[({[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}thioxomethoxy)methyl]oxolane-3,4-diol;2-{6-[((3)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(cyclobutylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,SR)-5-{[(cyclopropylamino)thioxomethoxy]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[(prop-2-enylamino)thioxomethoxy]methyl}oxolane-3,4-diol;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-((1S,2S)-2-hydroxycyclopentyl)carboxamide;{(5-{6[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-((1R,2R)-2-hydroxycyclopentyl)carboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[((1R,2R)-2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[((1S,2S)-2-hydroxycyclopentyl)amino]thioxomethoxy}methyl)oxolane-3,4-diol;2-{[5-{6-[(3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}cyclopentanecarboxylicacid;3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}(2S,3R)bicyclo[2.2.1 ]hept-5-ene-2-carboxylic acid;3-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylarnino}propanoic acid;2-{[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]carbonylamino}acetic acid,5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2R,3R,4R,5R)-4-acetyloxy-2-[(N-methylcarbamoyloxy)methyl]oxolan-3-ylacetate;[(5-{6-[((3R)oxolan-3-yl)anmino]-2-chloropurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-methylcarboxamide,[(5-{6-[((3R)oxolan-3-yl)amino]-2-chloropurin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methoxy]-N-cyclopentylcarboxamide;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl]methoxycarboxamide;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methy]cyclopentyloxycarboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[methoxythioxomethyl)amino]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-{[cyclopentyloxythioxomethyl)amino]methyl}oxolane-3,4-diol;[(5-{6-[((3R)oxolan-3-yl)arnino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methythio]-N-methylcarboxamide;[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methythio]-N-cyclopentylcarboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-{[(methylamino)thioxomethylthio]methyl}oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-{[(cyclopentylamino)thioxomethylthio]methyl}oxolane-3,4-diol;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3 S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](methylamino)carboxamide;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](cyclopentylamino)carboxamide;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(methylamino)thioxomethyl]amino}methyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,2R,3R,5R)-5-({[(cyclopentylamino)thioxomethyl]amino}methyl)oxolane-3,4-diol;N-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R,5R)-3,4-dihydroxyoxolan-2-yl)methyl](ethylamino)carboxamide;and3-[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(3S,2R,4R)-3,4-dihydroxyoxolan-2-yl)methyl]-1,3-oxazolin-2-one.
 49. A method for modifying cardiac activity in amammal experiencing a heart electrical disorder that can be treated bystimulating an A₁ adenosine receptor comprising the administration of atherapeutically effective amount of the composition of claim 1 to themammal.
 50. A method for modifyg mammalian adipocyte function bystimulating an A₁ adenosine receptor comprising administering atherapeutically effective amount of the composition of claim 1 to themammal.
 51. A method to restore sensitivity and efficacy of insulin in amammal by stimulating an A₁ adenosine receptor comprising theadministration of a therapeutically effective amount of a composition ofclaim 1 to the mammal.
 52. A method for providing a mammal with centralnervous system neuroprotection by stimulating an A₁ adenosine receptorcomprising administering a therapeutically effective amount of thecomposition of claim 1 to the mammal.
 53. A method for providing amammal with cardiomyocyte protection from ischemia by stimulating an A₁adenosine receptor comprising administering a therapeutically effectiveamount of the composition of claim 1 to the mammal.
 54. The method ofclaim 49 or 50 or 51 or 52 or 53 wherein the therapeutically effectiveamount ranges from about 0.01 to about 100 mg/kg weight of the mammal.55. The method of claim 49 wherein the composition is administered tothe mammal experiencing a heart electrical disorder selected from thegroup consisting of supraventricular tachycardias, atrial fibrillation,atrial flutter, and AV nodal re-entrant tachycardia.
 56. The method ofclaim 50 or 51 wherein the composition is administered to a mammalexperiencing a disorder selected from the group consisting of diabetesand obesity.
 57. The method of claim 52 wherein the composition isadministered to a mammal experiencing an central nervous system disorderselected from the group consisting of epilepsy, and stroke.
 58. Themethod of claim 53 wherein the composition is administered to a mammalexperiencing an ischemic event in the heart selected from the groupconsisting of stable angina, unstable angina, cardiac transplant, andmyocardial infarction.
 59. The method of claim 49 or 50 or 51 or 52 or53 wherein the mammal is a human.
 60. A pharmaceutical composition ofmatter comprising the composition of claim 1 and one or morepharmaceutical excipients.
 61. The pharmaceutical composition of matterof claim 60 wherein the pharmaceutical composition is in the form of asolution.
 62. The pharmaceutical composition of matter of claim 60wherein the pharmaceutical composition is in the form of a tablet.